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Beer, Bones and Hops

Jacob Schor

March 2010


What does an 18th century British brewery have to do with our current osteoporosis treatments, particularly for women with breast cancer?  There is a connection but it’ll take some explaining. 

Beer does not travel well.  Even with modern refrigeration, shipping is still problematic.  Back in the late 1700s, it was almost impossible.  The desire to ship beer to the far-flung corners of the English Empire presented British brewers with a major challenge.  They wanted to ship beer to India and also supply sailors on His Majesty’s ships during their long voyages. The Suez Canal was yet to be built; to reach India, ships sailed around the Cape of Good Hope, and then north into the tropics. Beer could not survive the heat and motion of the journey.  On arrival in India it was undrinkable.

Toward the end of the 18th century, a British brewer named George Hodgson solved the India problem. He created a special style of beer, brewing it to a higher alcohol content and using far more hops than was customary.  This formula protected the beer from spoilage and masked any stale flavors that developed in transit. Hodgson’s recipe and method of brewing beer became known as India Pale Ale or IPA, a name that has survived until today.

To understand this story we also need to talk about hops. Hops are the female flower clusters of Humulus lupulus. Hops are used in beer making, imparting a bitter, tangy flavor.  Hops are also used in herbal medicine as a soporific similar to valerian.  Beer making though has driven cultivation of this plant for thousands of years. Pliny the Elder (23 CE –79) mentioned hops in his Naturalis Historia nearly two thousand years ago. Due to centuries of careful cultivation for the purpose of producing better beers, hundreds of distinct hops cultivars exist.  Measures to maintain the purity of these cultivars go back centuries, at least to 1603, when an act was passed in England entitled “An Acte for avoyding of deceit in selling, buying or spending corrupt and unwholesome Hoppes”. Rules strictly prohibit male plants in the hops fields that might accidentally cross pollinate any plants

Hops contain several chemicals that are of great interest to us.  First, they contain significant quantities of bioavailable silicon.  Second, they contain chemicals that are converted into phytoestrogens in the intestine.  Third, they contain chemicals that trigger apoptosis in cancer cells.  Fourth, some of these chemicals are aromatase inhibitors that inhibit progression of hormone dependent cancers.

Silicon has become an important nutrient over the last few years for treating osteoporosis.  An early hint that beer might offer health benefits appeared in Kondo’s 2004 review paper written by the Kirin Brewing Company of Japan that examined the non-alcoholic components of beer. “A series of studies using animal models have shown that beer may prevent carcinogenesis and osteoporosis;”


An April 2009 paper in the American Journal of Clinical Nutrition reported that compared to nondrinkers, both male and female drinkers had denser bones.  Men who consumed 1-2 drinks a day of alcohol or beer had 3.4-4.5% greater hip bone mineral density (BMD.)  Postmenopausal women consuming more than 2 drinks per day had even greater hip and spine BMD (5-8.3%).  Drinking more than 2 drinks a day did not appear to convey added benefit to men, it actually lowered their BMD. After adjustment for silicon intake, all intergroup differences for beer were no longer significant.”

An October 2009 article in the journal Nutrition reported on a Spanish study. Data were collected on “1697 healthy women… 710 were premenopausal, 176 were perimenopausal, and 811 were postmenopausal. The women recruited completed a questionnaire that contained detailed sections on current cigarette, alcohol, caffeine, and nutrient consumption.” The researchers used ultrasound transmission speeds through bone to judge density.  The found, “Quantitative bone ultrasound values were greater in the beer drinkers compared with the no beer and/or wine drinkers.”

We’ve long known that silicon was essential for strong connective tissue.  Just look at all the silicon containing products at Vitamin Cottage and their promise to improve brittle fingernails and hair as well as erase facial wrinkles. 


A double blinded, placebo controlled human clinical trial using silicon in the form of orthosilicic acid (OSA) in postmenopausal women was published in June 2008. “Over 12-months, 136 women … completed the study and received, daily, 1000 mg Ca and 20 mcg cholecalciferol (Vit D3) and three different ch-OSA doses (3, 6 and 12 mg Si) or placebo. … Overall, there was a trend for ch-OSA to confer some additional benefit to Ca and Vit D3 treatment, especially for markers of bone formation, …. Combined therapy of ch-OSA and Ca/Vit D3 had a potential beneficial effect on bone collagen compared to Ca/Vit D3 alone which suggests that this treatment is of potential use in osteoporosis.”

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A June 2009 rat study also suggests silicon may be of use, “… Si[licon] supplementation produced positive effects on bone mineral density in Ca-deficient OVX [ovariectomized] rats by reducing bone resorption.” Nevertheless, these results should be considered with caution as the doses they used were quite high, 500 mg/Kg body weight.

Silicon is found in clinically relevant amounts in a number of foods but absorption varies. For example 64% of the silicon found in alcohol-free beer is absorbed while only 4% of the silicon in bananas is.  

Beer, it turns out, is an excellent source of silicon. A 2004 article in The British Journal of Nutrition analyzed silica content of 76 different regional English beers and absorption.  They found little variation in silicon content, they averaged about 19.2 mg/L and about 55% of the silica was absorbed, an absorption comparable to a liquid solution of orthosilicic acid (OSA).  


A recent article by Bamforth and Casey published online in February 2010 found a greater variation in beers in the United States. The researchers analyzed 100 commercial beers and found the silicon content ranged from 6.4 mg/L to 56.5 mg/L, with an average of 30 mg/L. Two beers are the equivalent of just under a half-liter; a person could easily get a substantial dose of silicon from drinking just a few beers.  Drinking beer for your health requires a careful balance.  While a beer or so may be good, more than two drinks a day is considered bad for your health.  So one would want to choose a beer with a high silicon content.  India Pale Ales as a group have the highest silicon contents of any commercial beer.


      • Indian Pale Ale (IPA): 41.2 mg/L
      • Ales: 32.8 mg/L
      • Pale Ale: 36.5 mg/L
      • Sorghum: 27.3 mg/L
      • Lagers: 23.7 mg/L
      • Wheat: 18.9 mg/L
      • Light lagers: 17.2 mg/L
      • Non Alcoholic: 16.3 mg/L


The high silicon content may explain at least in part why beer drinkers have stronger bones but it isn’t this simple.  Other chemicals found in hops act as phytoestrogens. 

In fact hops may be useful in reducing menopausal hot flashes because of these phytoestrogens.  A 2005 paper compared the in vitro extrogenic effects of hops with those of red clover (Trifolium pratense) predicting that both might be useful to alleviated symptoms.

A 2006 paper found the phytoestrogen, 8-prenylnaringenin, isolated from hops useful in preventing hotflash like symptoms in animals with surgically induced menopause.   The first prospective, randomized, double-blind, placebo-controlled study using a hop extract to alleviate menopausal symptoms in women was published in May 2006.

January 2006: The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties.

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These phytoestrogens may contribute to greater bone density.

These chemicals found in hops may also lower risk of breast cancer.  It appears that some of them act as aromatase inhibitors lowering levels of estrogens.   An April 2006 paper tells us that both the prenylflavonoids isolated from hops and from various beers that the researchers tested had significant effect inhibiting aromatase action.    This action would account for some of the anticancer effect of hops.

Studies have focused mainly on xanthohumol, the most abundant prenylated chalcone in hops extract. However, during beer brewing and after drinking, the xanthohumol breaks down into different metabolites, including isoxanthohumol and 8-prenylnaringenin.  When these three chemicals,  xanthohumol, isoxanthohumol and 8-prenylnaringenin were tested on breast cancer cells, all three chemicals  inhibited aromatase activity and thus, estrogen formation. Additionally, the three compounds decreased breast cancer cell line proliferation and induced apoptosis. Adding estrogen to the cells neutralized the anti-proliferative effect of these compounds, suggesting that their mechanism of action involved estrogen depletion.    These same chemicals are apparently effective against a wider range of cancers.

A quick literature search suggests chemicals could play an active role in treating colorectal adenocarcinoma,  hepatocellular carcinoma, melanoma, prostate cancer, and Burkitt lymphoma.

Of note is a February 2007 article in Cancer Letters that tells us that xanthohumol, derived from hops, not only induces apoptosis in prostate cancer cells but it also inhibits NF-kappaB activation.   We could extrapolate from the NF-KappaB inhibition to create a long list or potential uses. 

There are situations where we might argue in favor of regular consumption of India Pale Ale, for example a menopausal, osteoporotic patient at high risk for breast cancer.  The potential benefit of this prescription needs to be balanced by the increased risks posed by the alcohol consumed, but then again those alcohol free beers are increasingly drinkable.  Conceivably a high hops, high silicon, high xanthohumol and low alcohol beer could be developed.  With simple manipulations in the brewing process xanthohumol levels of beer can be increased up to 10 mg/L.

Silicon is now one of the many tools we consider for treating osteoporosis.  Past articles have featured the benefit of unipedal standing, or what is now referred to as Flamingo Therapy.  This program may need updating.  Instead telling people to stand on each foot for a minute twice a day, perhaps we should say, “Stand on one foot while drinking a bottle of India Pale Ale, then switch feet and open another bottle.”


Granted that last paragraph was written tongue in cheek.  We aren’t quite ready to suggest this yet.  That is because the frequency of falls is a far stronger predictor of osteoporotic fractures than bone density is.  Drinking beer will most likely increase falls far more significantly than it will increase bone density.  In the end, beer drinkers will not come out ahead.  That is unless they develop a taste for non-alcoholic brews.  What this research does point to is the potential benefit that might be derived from concentrates isolated from beer and not that we should encourage unhealthy habits in ourselves and others. 


Biofactors. 2004;22(1-4):303-10.

Beer and health: preventive effects of beer components on lifestyle-related diseases.

Kondo K.

Research and Development Department, Kirin Brewery Company, Limited, 10-1, Shinkawa 2-Chome, Chuo-ku, Tokyou, 104-8288, Japan.

It has been demonstrated that the light-to-moderate consumption of alcoholic beverages is associated with significant reductions in all-cause and particularly cardiovascular mortality. While the inverse association between red-wine consumption and cardiovascular risk is globally recognized as the French paradox, many epidemiological studies have concluded that beer and red wine are equally beneficial. Moderate alcohol intake improves lipoprotein metabolism and lowers cardiovascular mortality risk. The question now is whether additional health benefits associated with the non-alcohol components in beer may be expected. This article summarizes the results of the latest studies on the health benefits of beer while referring to our recent results, which demonstrate the preventive effects of beer and its components on lifestyle-related diseases. A series of studies using animal models have shown that beer may prevent carcinogenesis and osteoporosis; beer provides plasma with significant protection from oxidative stress; and isohumulones, the bitter substances derived from hops, may prevent and improve obesity and type-2 diabetes, improve lipid metabolism, and suppress atherosclerosis. Further studies are needed to clarify the components in addition to isohumulones that are responsible for these beneficial effects of beer, and the underlying mechanisms must be addressed.

Am J Clin Nutr. 2009 Apr;89(4):1188-96. Epub 2009 Feb 25.

Effects of beer, wine, and liquor intakes on bone mineral density in older men and women.

Tucker KL, Jugdaohsingh R, Powell JJ, Qiao N, Hannan MT, Sripanyakorn S, Cupples LA, Kiel DP.

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.

Comment in:

BACKGROUND: Moderate intake of alcohol has been reported to have beneficial effects on bone. However, different classes of alcoholic beverages have not been investigated. OBJECTIVE: Our aim was to determine the association between intake of total alcohol or individual alcoholic beverages and bone mineral density (BMD). DESIGN: Adjusting for potential confounding factors, we examined alcohol intakes and BMD at 3 hip sites and the lumbar spine in 1182 men and in 1289 postmenopausal and 248 premenopausal women in the population-based Framingham Offspring cohort (age: 29-86 y). RESULTS: Men were predominantly beer drinkers, and women were predominantly wine drinkers. Compared with nondrinkers, hip BMD was greater (3.4-4.5%) in men consuming 1-2 drinks/d of total alcohol or beer, whereas hip and spine BMD were significantly greater (5.0-8.3%) in postmenopausal women consuming >2 drinks/d of total alcohol or wine. Intake of >2 drinks/d of liquor in men was associated with significantly lower (3.0-5.2%) hip and spine BMD than was intake of 1-2 drinks/d of liquor in men. After adjustment for silicon intake, all intergroup differences for beer were no longer significant; differences for other alcohol sources remained significant. Power was low for premenopausal women, and the associations were not significant. CONCLUSIONS: Moderate consumption of alcohol may be beneficial to bone in men and postmenopausal women. However, in men, high liquor intakes (>2 drinks/d) were associated with significantly lower BMD. The tendency toward stronger associations between BMD and beer or wine, relative to liquor, suggests that constituents other than ethanol may contribute to bone health. Silicon appears to mediate the association of beer, but not that of wine or liquor, with BMD. Other components need further investigation.

Nutrition. 2009 Oct;25(10):1057-63. Epub 2009 Jun 13.

Effect of beer drinking on ultrasound bone mass in women.

Pedrera-Zamorano JD, Lavado-Garcia JM, Roncero-Martin R, Calderon-Garcia JF, Rodriguez-Dominguez T, Canal-Macias ML.

Department of Nursing, University of Extremadura, Caceres, Spain.

OBJECTIVE: To study the effect of beer consumption on bone mass in a group of healthy women, by using phalangeal bone ultrasound to evaluate the amplitude-dependent speed of sound. METHODS: This was a cross-sectional study of 1697 healthy women (mean age 48.4 y, body mass index (BMI) 19.0-32.0 kg/m(2)), recruited in a clinical convenience sample and screened for the existence of disease and/or medication that would affect calcium metabolism. Of this total, 710 were premenopausal, 176 were perimenopausal, and 811 were postmenopausal. The women recruited completed a questionnaire that contained detailed sections on current cigarette, alcohol, caffeine, and nutrient consumption. In terms of current alcohol intake, the subjects were classified as moderate drinkers, light drinkers, and nondrinkers. Drinkers were also analyzed according to the kind of alcohol consumed: wine or beer. RESULTS: Quantitative bone ultrasound values were greater in the beer drinkers compared with the no beer and/or wine drinkers. Taking the amplitude-dependent speed of sound as a dependent variable, and age, BMI, gonadal status, intake of beer and wine, and number of cigarettes per day as independent variables, we found age (beta = -1.52), BMI (beta = -3.86), gonadal status (beta = -27.47), and beer intake (beta = 1.06) to be significant. CONCLUSION: The greater bone density found in women beer drinkers might be a result of the phytoestrogen content of this alcoholic drink; this requires further investigation.

PMID: 19527924 [PubMed - indexed for MEDLINE]

BMC Musculoskelet Disord. 2008 Jun 11;9:85.

Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial.

Spector TD, Calomme MR, Anderson SH, Clement G, Bevan L, Demeester N, Swaminathan R, Jugdaohsingh R, Berghe DA, Powell JJ.

Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, Kings College, London, UK.

BACKGROUND: Mounting evidence supports a physiological role for silicon (Si) as orthosilicic acid (OSA, Si(OH)4) in bone formation. The effect of oral choline-stabilized orthosilicic acid (ch-OSA) on markers of bone turnover and bone mineral density (BMD) was investigated in a double-blind placebo-controlled trial. METHODS: Over 12-months, 136 women out of 184 randomized (T-score spine < -1.5) completed the study and received, daily, 1000 mg Ca and 20 microg cholecalciferol (Vit D3) and three different ch-OSA doses (3, 6 and 12 mg Si) or placebo. Bone formation markers in serum and urinary resorption markers were measured at baseline, and after 6 and 12 months. Femoral and lumbar BMD were measured at baseline and after 12 months by DEXA. RESULTS: Overall, there was a trend for ch-OSA to confer some additional benefit to Ca and Vit D3 treatment, especially for markers of bone formation, but only the marker for type I collagen formation (PINP) was significant at 12 months for the 6 and 12 mg Si dose (vs. placebo) without a clear dose response effect. A trend for a dose-corresponding increase was observed in the bone resorption marker, collagen type I C-terminal telopeptide (CTX-I). Lumbar spine BMD did not change significantly. Post-hoc subgroup analysis (baseline T-score femur < -1) however was significant for the 6 mg dose at the femoral neck (T-test). There were no ch-OSA related adverse events observed and biochemical safety parameters remained within the normal range. CONCLUSION: Combined therapy of ch-OSA and Ca/Vit D3 had a potential beneficial effect on bone collagen compared to Ca/Vit D3 alone which suggests that this treatment is of potential use in osteoporosis. NTR 1029.

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Biol Trace Elem Res. 2009 Jun;128(3):239-47. Epub 2008 Nov 27.

Silicon supplementation improves the bone mineral density of calcium-deficient ovariectomized rats by reducing bone resorption.

Kim MH, Bae YJ, Choi MK, Chung YS.

Department of Food and Nutrition, Kangwon National University, Samcheok-si, Gangwondo, South Korea.

The purpose of this study was to investigate the effect of silicon (Si) supplementation on bone mineral density (BMD) and bone metabolism parameters relative to calcium (Ca) intake levels in ovariectomized rats. A total of 72 female Wistar rats (6 weeks) were ovariectomized (OVX) and divided into six groups, and Si (500 mg of Si per kilogram of feed) was or was not administered with diets containing various levels of Ca (0.1%, 0.5%, and 1.5%) for 10 weeks. The groups were as follows: (1) Ca-deficient group (0.1% Ca), (2) Ca-deficient with Si supplementation group, (3) adequate Ca group (0.5% Ca), (4) adequate Ca with Si supplementation group, (5) high Ca group (1.5% Ca), and (6) high Ca with Si supplementation group. Si supplementation significantly increased the BMD of the femur and tibia in Ca-deficient OVX rats, while no change was observed with Si supplementation in the BMD of the spine, femur, and tibia in the adequate and high Ca groups. Serum alkaline phosphatase and osteocalcin levels were not affected by Si supplementation or Ca intake levels. C-telopeptide type I collagen levels were significantly decreased as a result of Si supplementation in Ca-deficient OVX rats. In summary, Si supplementation produced positive effects on bone mineral density in Ca-deficient OVX rats by reducing bone resorption. Therefore, Si supplementation may also prove to be helpful in preventing osteoporosis in postmenopausal women whose calcium intake is insufficient.

PMID: 19034393 [Pub

Br J Nutr. 2009 Sep;102(6):825-34. Epub 2009 Apr 9.

The comparative absorption of silicon from different foods and food supplements.

Sripanyakorn S, Jugdaohsingh R, Dissayabutr W, Anderson SH, Thompson RP, Powell JJ.

Gastrointestinal Laboratory, The Rayne Institute (King's College London), St Thomas' Hospital, London SE1 7EH, UK.

Dietary Si (orthosilicic acid; OSA) appears important in connective tissue health, and although the sources and intakes of Si are well established, its absorption is not. Si absorption was measured from eight high-Si-containing sources: alcohol-free beer; OSA solution (positive control); bananas; green beans; supplemental choline-stabilised OSA (ChOSA); supplemental monomethyl silanetriol (MMST); supplemental colloidal silica (CS); magnesium trisilicate British Pharmacopoeia antacid (MTBP). Two of the supplements and the antacid were pre-selected following an in vitro dissolution assay. Fasting, healthy subjects (CS, n 3; others, n > or = 5) each ingested two of the sources separated by a 1-week wash-out period. Blood and urine were collected and measured for total Si concentrations by inductively coupled plasma optical emission spectrometry. Absorption, based on urinary Si excretion, was highest for MMST and alcohol-free beer (64% of dose), followed by green beans (44%), OSA (43%), ChOSA (17%), bananas and MTBP (4%) and CS (1%). Peak serum concentrations occurred by 0.5 h for MMST and green beans, 1.5 h for OSA and alcohol-free beer, 2 h for ChOSA and CS, and 4 h for MTBP. Area under the serum curves correlated positively with urinary Si output (r 0.82; P < 0.0001). Absorption of Si from supplements and antacids was consistent with their known chemical speciation and kinetics of dissolution under simulated gastrointestinal conditions. Monomeric silicates were readily absorbed, while particulate silicates were decreasingly well absorbed with increasing polymerisation. The present results highlight the need to allow for relative absorption of Si from different foods or supplements in subsequent epidemiological and intervention studies.

PMID: 1935627

Br J Nutr. 2004 Mar;91(3):403-9.

The silicon content of beer and its bioavailability in healthy volunteers.

Sripanyakorn S, Jugdaohsingh R, Elliott H, Walker C, Mehta P, Shoukru S, Thompson RP, Powell JJ.

Gastrointestinal Laboratory, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.

Dietary Si, as soluble orthosilicic acid (OSA), may be important for the growth and development of bone and connective tissue. Beer appears to be a major contributor to Si intake, although the Si content of beer and its bioavailability in human subjects have not been well established. Here we investigated the Si content of different beers and then estimated Si absorption from beer in healthy volunteers. The Si content of seventy-six different beers was estimated using inductively coupled plasma optical emission spectrometry and one of the beers, used in the ingestion study, was ultrafiltered to determine OSA content. Next, following the ingestion of 0.6 litres beer (22.5 mg Si; 4.6 % (v/v) ethanol), serum and urinary Si levels were measured in nine healthy volunteers over a 6 h period. A solution of OSA was similarly investigated as a positive control and water and 4.6 % ethanol as negative controls. The mean Si level of beer was 19.2 (sd 6.6) mg/l; the median Si level was 18.0 mg/l. There was no significant difference in the Si levels of the different beers by geographical origin or type of beer. Serum and urinary Si levels increased considerably following the ingestion of beer or a solution of OSA but not with the ingestion of either 4.6 % ethanol or water. The ultrafilterability of Si from beer (about 80 %) and its absorption in volunteers (about 55 %) was comparable with that of a solution of OSA suggesting that Si in beer is present chiefly in a monomeric form and is readily bioavailable.

Journal of the Science of Food and Agriculture

Volume 90 Issue 5, Pages 784 - 788

Published Online: 8 Feb 2010Research Article

Silicon in beer and brewing

Troy R Casey, Charles W Bamforth *

Department of Food Science & Technology, University of California, Davis, CA 95616-8598, USA

email: Charles W Bamforth (

*Correspondence to Charles W Bamforth, Department of Food Science & Technology, University of California, Davis, CA 95616-8598, USA.


BACKGROUND: It has been claimed that beer is one of the richest sources of silicon in the diet; however, little is known of the relationship between silicon content and beer style and the manner in which beer is produced. The purpose of this study was to measure silicon in a diversity of beers and ascertain the grist selection and brewing factors that impact the level of silicon obtained in beer.

RESULTS: Commercial beers ranged from 6.4 to 56.5 mg L-1 in silicon. Products derived from a grist of barley tended to contain more silicon than did those from a wheat-based grist, likely because of the high levels of silica in the retained husk layer of barley. Hops contain substantially more silicon than does grain, but quantitatively hops make a much smaller contribution than malt to the production of beer and therefore relatively less silicon in beer derives from them. During brewing the vast majority of the silicon remains with the spent grains; however, aggressive treatment during wort production in the brewhouse leads to increased extraction of silicon into wort and much of this survives into beer.

CONCLUSION: It is confirmed that beer is a very rich source of silicon. Copyright © 2010 Society of Chemical Industry

Received: 3 July 2009; Revised: 28 November 2009; Accepted: 1 December 2009

Digital Object Identifier (DOI)

10.1002/jsfa.3884  About DOI

J Agric Food Chem. 2005 Aug 10;53(16):6246-53.

Comparison of the in vitro estrogenic activities of compounds from hops (Humulus lupulus) and red clover (Trifolium pratense).

Overk CR, Yao P, Chadwick LR, Nikolic D, Sun Y, Cuendet MA, Deng Y, Hedayat AS, Pauli GF, Farnsworth NR, van Breemen RB, Bolton JL.

Department of Medicinal Chemistry and Pharmacognosy, UIC/NIH Center for Botanical Dietary Supplements Research, College of Pharmacy, M/C 781, University of Illinois, 833 South Wood Street, Chicago, Illinois 60612, USA.

Because the prevailing form of hormone replacement therapy is associated with the development of cancer in breast and endometrial tissues, alternatives are needed for the management of menopausal symptoms. Formulations of Trifolium pratense L. (red clover) are being used to alleviate menopause-associated hot flashes but have shown mixed results in clinical trials. The strobiles of Humulus lupulus (hops) have been reported to contain the prenylflavanone, 8-prenylnaringenin (8-PN), as the most estrogenic constituent, and this was confirmed using an estrogen receptor ligand screening assay utilizing ultrafiltration mass spectrometry. Extracts of hops and red clover and their individual constituents including 8-PN, 6-prenylnaringenin (6-PN), isoxanthohumol (IX), and xanthohumol (XN) from hops and daidzein, formononetin, biochanin A, and genistein from red clover were compared using a variety of in vitro estrogenic assays. The IC50 values for the estrogen receptor alpha and beta binding assays were 15 and 27 microg/mL, respectively, for hops and 18.0 and 2.0 microg/mL, respectively, for the red clover extract. Both of the extracts, genistein, and 8-PN activated the estrogen response element (ERE) in Ishikawa cells while the extracts, biochanin A, genistein, and 8-PN, significantly induced ERE-luciferase expression in MCF-7 cells. Hop and red clover extracts as well as 8-PN up-regulated progesterone receptor (PR) mRNA in the Ishikawa cell line. In the MCF-7 cell line, PR mRNA was significantly up-regulated by the extracts, biochanin A, genistein, 8-PN, and IX. The two extracts had EC50 values of 1.1 and 1.9 microg/mL, respectively, in the alkaline phosphatase induction assay. On the basis of these data, hops and red clover could be attractive for the development as herbal dietary supplements to alleviate menopause-associated symptoms.

J Endocrinol. 2006 Nov;191(2):399-405.

The hop phytoestrogen, 8-prenylnaringenin, reverses the ovariectomy-induced rise in skin temperature in an animal model of menopausal hot flushes.

Bowe J, Li XF, Kinsey-Jones J, Heyerick A, Brain S, Milligan S, O'Byrne K.

Division of Reproduction and Endocrinology, King's College London, 2.36D New Hunt's House, Guy's Campus, London SE1 1UL, UK.

The mechanisms underlying menopausal hot flushes are poorly understood, although it is generally assumed they result from disturbances of thermoregulatory centres in the hypothalamus. 8-Prenylnaringenin (8-PN) has been identified as a potent phytoestrogen in hops (Humulus lupulus) and there are claims that hop-containing preparations can reduce hot flushes. We have investigated the site of action of 8-PN in a rat model of menopausal hot flushes, in which the tail skin temperature (TST) is increased after oestrogen withdrawal induced by ovariectomy. Daily s.c. administration of either 17beta-oestradiol (E2; 4 microg/kg) or 8-PN (400 microg/kg) significantly reduced the elevated TST after 2 days of treatment. Subcutaneous co-administration of either E2 or 8-PN with the oestrogen receptor (ER) antagonist, ICI 182,780 (200 microg/kg), which is thought not to cross the blood-brain barrier, completely blocked the effect of E2 and 8-PN on TST. The ERalpha- and ERbeta-specific agonists, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (100 microg/kg) and 2,3-bis(4-hydroxyphenyl)-propionitrile (60 microg/kg) respectively, both significantly reversed the raised TST in ovariectomised rats. These observations suggest that the regulation of the vasomotor response by oestrogens and phytoestrogens is mediated, at least in part, by peripheral mechanisms involving both ERalpha and ERbeta.

Maturitas. 2006 May 20;54(2):164-75.

A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts.

Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D.

Laboratory of Pharmacognosy and Phytochemistry, Ghent University-UGent, Harelbekestraat 72, 9000, and Department of Gynaecological Oncology, Ghent University Hospital, Ghent, Belgium.

OBJECTIVES: To examine the efficacy of a hop extract enriched in 8-prenylnaringenin (8-PN, the phytoestrogen in hops, Humulus lupulus L.) on relief of menopausal discomforts. METHODS: A prospective, randomized, double-blind, placebo-controlled study over 12 weeks with 67 menopausal women, who were administered a hop extract standardized on 8-PN (100 or 250 microg). The responses were determined by means of a modified Kupperman index (KI) and a patients' questionnaire. RESULTS: All groups, including placebo, showed a significant reduction of the KI both after 6 weeks and after 12 weeks. The hop extract at 100 microg 8-PN was significantly superior to placebo after 6 weeks (P=0.023) but not after 12 weeks (P=0.086). No dose-response relationship could be established, as the higher dose (250 microg) was less active than the lower dose both after 6 weeks and after 12 weeks. Still, a trend for a more rapid decrease of KI was noticed for both active groups as compared to placebo. In particular, the decrease in hot flush score (isolated from the KI) was found significant for both treatment groups after 6 weeks (P<0.01) with respect to placebo. Results of the patients' questionnaire were consistent with those of the KI, with the most pronounced effects being observed for the 100-microg treatment. CONCLUSIONS: Daily intake of a hop extract, standardized on 8-PN as a potent phytoestrogen, exerted favorable effects on vasomotor symptoms and other menopausal discomforts. Hop-derived prenylated flavonoids may provide an attractive addition to the alternative treatments available for relief of hot flushes and other menopausal discomforts.

Phytomedicine. 2006 Jan;13(1-2):119-31. Epub 2005 Jul 1.

The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties.

Chadwick LR, Pauli GF, Farnsworth NR.

UIC/NIH Center for Botanical Dietary Supplements Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.

As the population ages, there is an ever-increasing need for therapeutic agents that can be used safely and efficaciously to manage symptoms related to postmenopausal estrogen deficiency. Endogenous estrogens, e.g., 17beta-estradiol, of exogenous mammalian origin, e.g., horses, have long been used to manage such symptoms. There are more than 20 different classes of phytochemicals that have demonstrated affinity for human estrogen receptors in vitro. Some studies on exogenous estrogenic substances of botanical origin (phytoestrogens), such as standardized formulations of plant extracts with in vitro and in vivo estrogenic activity from soy (Glycine max Merill.) and red clover (Trifolium pratense L.), suggest clinical efficacy. Few clinical data for phytoestrogens other than isoflavonoids are available. In an exhaustive review of the literature through 2003, only two clinical trials were identified that were designed to evaluate the effect of hops (Humulus lupulus L.) on symptoms related to menopause. Folkloric, chemical, and biological literature relating primarily to the use of hops for their estrogenic activity, and two human clinical trials, are reviewed.

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J Agric Food Chem. 2006 Apr 19;54(8):2938-43.

Effect of hop (Humulus lupulus L.) flavonoids on aromatase (estrogen synthase) activity.

Monteiro R, Becker H, Azevedo I, Calhau C.

Department of Biochemistry, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.

The aim of this work was to study the effect of the prenylflavonoids xanthohumol, isoxanthohumol, and 8-prenylnaringenin on the activity and expression of the enzyme aromatase (estrogen synthase). The effect of different kinds of beer containing these prenylflavonoids was also tested. Aromatase activity was determined by measuring the release of tritiated water during the conversion of [(3)H]androstenedione to estrone. Aromatase expression was determined by RT-PCR. This assay was carried out in choriocarcinoma-derived JAR cells. The tested prenylflavonoids were able to inhibit estrogen formation, and their IC(50) values were determined, although no effect on aromatase expression was found. Lager beer, alcohol-free beer, stout beer, and xanthohumol-rich stout beer (200 microL/mL) significantly decreased aromatase activity. In conclusion, prenylflavonoids are able to modulate aromatase activity, decreasing estrogen synthesis, with relevance for the prevention and treatment of estrogen-dependent disorders such as breast cancer.

J Steroid Biochem Mol Biol. 2007 Jun-Jul;105(1-5):124-30. Epub 2007 Jul 23.

Modulation of breast cancer cell survival by aromatase inhibiting hop (Humulus lupulus L.) flavonoids.

Monteiro R, Faria A, Azevedo I, Calhau C.

Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.

Hop flavonoids are being regarded as attractive molecules to prevent or treat certain forms of cancer. Studies have focused mainly on xanthohumol, the most abundant prenylated chalcone existing in hops extract. However, during the production of beer, or after its ingestion, xanthohumol originates different metabolites, among which isoxanthohumol and 8-prenylnaringenin. The aim of this work was to study the effect of the prenylflavonoids xanthohumol, isoxanthohumol and 8-prenylnaringenin on the breast cancer Sk-Br-3 cell line proliferation, apoptosis and activity of the enzyme aromatase (estrogen synthase). Aromatase activity was determined by a tritiated water assay, cell proliferation was assessed by [(3)H]thymidine incorporation, sulforhodamine B protein measurement and Ki-67 immunostaining and apoptosis was determined by TUNEL. Our results show that all tested prenylflavonoids were able to inhibit aromatase activity and thus, estrogen formation. Additionally, breast cancer cell line proliferation was decreased and apoptosis induced by all three compounds. The presence of 17beta-estradiol in treatment medium was able to revert the effect of the prenylflavonoids on cellular proliferation. These observations strengthen the idea that hop flavonoids may have anti-breast cancer effects and shed new light on a possible mechanism of action by which these effects occur, namely through their ability to decrease estrogen synthesis.

PMID: 17643984 [PubMed - indexed for M

Food Chem Toxicol. 2009 Jan 15. [Epub ahead of print]

Hop proanthocyanidins induce apoptosis, protein carbonylation, and cytoskeleton disorganization in human colorectal adenocarcinoma cells via reactive oxygen species.

Chung WG, Miranda CL, Stevens JF, Maier CS.

Department of Chemistry, Oregon State University Corvallis, Oregon 97331.

Proanthocyanidins (PCs) have been shown to suppress the growth of diverse human cancer cells and are considered as promising additions to the arsenal of chemopreventive phytochemicals. An oligomeric mixture of PCs from hops (Humulus lupulus) significantly decreased cell viability of human colon cancer HT-29 cells in a dose-dependent manner. Hop PCs, at 50 or 100 mug/ml, exhibited apoptosis-inducing properties as shown by the increase in caspase-3 activity. Increased levels of intracellular reactive oxygen species (ROS) was accompanied by an augmented accumulation of protein carbonyls. Mass spectrometry-based proteomic analysis in combination with 2-alkenal-specific immunochemical detection identified beta-actin and protein disulfide isomerase as major putative targets of acrolein adduction. Incubation of HT-29 cells with hop PCs resulted in morphological changes that indicated disruption of the actin cytoskeleton. PC-mediated hydrogen peroxide (H(2)O(2)) formation in the cell culture media was also quantified; but, the measured H(2)O(2) levels would not explain the observed changes in the oxidative modifications of actin. These findings suggest new modes of action for proanthocyandins as antitumorgenic agents in human colon cancer cells, namely, promotion of protein oxidative modifications and cytoskeleton derangement.

PMID: 19709606 [PubMe

Phytother Res. 2008 Nov;22(11):1465-8.

Inhibitory effects of xanthohumol from hops (Humulus lupulus L.) on human hepatocellular carcinoma cell lines.

Ho YC, Liu CH, Chen CN, Duan KJ, Lin MT.

Department of Bioengineering, Tatung University, Taipei, Taiwan.

Xanthohumol is one of the main flavonoids in hop extracts and in beer. Very few investigations of xanthohumol have studied hepatocellular carcinoma. In this study, the inhibitory effects of xanthohumol on human hepatocellular carcinoma cell lines were investigated. The IC(50) values of xanthohumol for two hepatocellular carcinoma cell lines and one normal hepatocyte cell line were 108, 166 and 211 microm, respectively. Normal murine hepatocyte cell line had more resistance to xanthohumol than hepatocellular carcinoma cell lines. Besides, the inhibitory effects of xanthohumol on human hepatocellular carcinoma cell lines were attributed to apoptosis as indicated in the results of flow cytometry, fluorescent nuclear staining and electrophoresis of oligonucleosomal DNA fragments. Hop xanthohumol was more efficient in the growth inhibition of hepatocellular carcinoma cell lines than the flavonoids silibinin and naringin from thistle and citrus. It was shown for the first time that xanthohumol from hops effectively inhibits proliferation of human hepatocellular carcinoma cells in vitro.

PMID: 18814205 [PubMe

Exp Mol Med. 2008 Jun 30;40(3):313-9.

Effect of xanthohumol on melanogenesis in B16 melanoma cells.

Koo JH, Kim HT, Yoon HY, Kwon KB, Choi IW, Jung SH, Kim HU, Park BH, Park JW.

Department of Biochemistry, Medical School and Institute for Medical Sciences, Chonbuk National University, Jeonju, Korea.

Xanthohumol (XH), the principal prenylflavonoid of the hop plant (Humulus lupulus L.), dose-dependently inhibited isobutylmethylxanthine (IBMX)-induced melanogenesis in B16 melanoma cells, with little cytotoxicity at the effective concentrations. Decreased melanin content was accompanied by reduced tyrosinase enzyme activity, protein and mRNA expression. The levels of tyrosinase-related protein 1 and 2 mRNAs were decreased by XH. XH also inhibited alpha-melanocyte stimulating hormone- or forskolin-induced increases in melanogenesis, suggesting an action on the cAMP-dependent melanogenic pathway. XH downregulated the protein and mRNA expression of microphthalmia-associated transcription factor (MITF), a master transcriptional regulator of key melanogenic enzymes. These results suggest that XH might act as a hypo-pigmenting agent through the downregulation of MITF in the cAMP-dependent melanogenic pathway.

Phytother Res. 2008 Feb;22(2):197-203.

Treatment of PC-3 and DU145 prostate cancer cells by prenylflavonoids from hop (Humulus lupulus L.) induces a caspase-independent form of cell death.

Delmulle L, Vanden Berghe T, Keukeleire DD, Vandenabeele P.

Ghent University-UGent, Faculty of Pharmaceutical Sciences, Laboratory of Pharmacognosy and Phytochemistry, B-9000 Ghent, Belgium.

Xanthohumol (X), isoxanthohumol (IX), 8-prenylnaringenin (8PN) and 6-prenylnaringenin (6PN), prenylflavonoids from hop (Humulus lupulus L.), were investigated for their cytotoxicity and the mechanism by which they exert cell death when incubated with prostate cancer cell lines PC-3 and DU145. All compounds induced cell death in the absence of caspase-3 activation and typical apoptotic morphological features. The general pan-caspase inhibitor zVAD-fmk could not protect this form of cell death. In addition, the formation of vacuoles was observed in PC-3 cells treated with IX and 6PN, and in DU145 treated with IX, 8PN and 6PN, which could suggest the induction of autophagy and consequent cell death. The results indicate that hop-derived prenylflavanones (IX, 8PN, 6PN), but not prenylchalcones (X) induce a caspase-independent form of cell death, suggested to be autophagy. Therefore, IX, 8PN and 6PN appear to be promising candidates for further investigation in prostate anticancer therapy.

Phytomedicine. 2006 Nov;13(9-10):732-4. Epub 2006 May 5.

Anti-proliferative properties of prenylated flavonoids from hops (Humulus lupulus L.) in human prostate cancer cell lines.

Delmulle L, Bellahcène A, Dhooge W, Comhaire F, Roelens F, Huvaere K, Heyerick A, Castronovo V, De Keukeleire D.

Ghent University-UGent, Faculty of Pharmaceutical Sciences, Laboratory of Pharmacognosy and Phytochemistry, and Ghent University Hospital, Department of Endocrinology, Belgium.

Chalcones xanthohumol (X) and desmethylxanthohumol (DMX), present in hops (Humulus lupulus L.), and the corresponding flavanones isoxanthohumol (IX, from X), 8-prenylnaringenin (8-PN, from DMX), and 6-prenylnaringenin (6-PN, from DMX), have been examined in vitro for their anti-proliferative activity on human prostate cancer cells PC-3 and DU145. X proved to be the most active compound in inhibiting the growth of the cell lines with IC50 values of 12.3+/-1.1 microM for DU145 and 13.2+/-1.1 microM for PC-3. 6-PN was the second most active growth inhibitor, particularly in PC-3 cells (IC50 of 18.4+/-1.2 microM). 8-PN, a highly potent phytoestrogen, exhibited pronounced anti-proliferative effects on PC-3 and DU145 (IC50 of 33.5+/-1.0 and 43.1+/-1.2 microM, respectively), and IX gave comparable activities (IC50 of 45.2+/-1.1 microM for PC-3 and 47.4+/-1.1 microM for DU145). DMX was the least active compound. It was evidenced for the first time that this family of prenylated flavonoids from hops effectively inhibits proliferation of prostate cancer cells in vitro.

Planta Med. 2007 Jul;73(8):755-61.

Ability of prenylflavanones present in hops to induce apoptosis in a human Burkitt lymphoma cell line.

Diller RA, Riepl HM, Rose O, Frias C, Henze G, Prokop A.

Institute of Technology for Biogenic Resources, Technical University of Munich, Straubing, Germany.

The identification of effective cancer preventive compounds from hops has become an important issue in public health-related research. We compared the antiproliferative and apoptosis-inducing effects of side chain variants of prenylflavanones, e. g., 8-prenylnaringenin (7) and 8-geranylnaringenin (10), which have been identified in hops (Humulus lupulus), and their synthetic variations 8-furanmethylnaringenin (8) and 8-cinnamylnaringenin (9). These were accessible by a Mitsunobu reaction and Claisen rearrangement. Flavanones 9 and 10 showed cytotoxic and apoptotic activities. Apoptosis was induced in a mitochondrial dependent manner. 8-Cinnamylnaringenin (9) displayed noticeably improved apoptotic effects when compared to 8-prenylnaringenin. The potential of 8-prenylnaringenin (7) is shown in an ex vivo experiment on a multi-drug resistant leukaemia blast.

Cancer Lett. 2007 Feb 8;246(1-2):201-9. Epub 2006 Mar 24.

Xanthohumol, a prenylflavonoid derived from hops induces apoptosis and inhibits NF-kappaB activation in prostate epithelial cells.

Colgate EC, Miranda CL, Stevens JF, Bray TM, Ho E.

Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR 97331, USA.

There is increasing evidence that certain natural compounds found in plants may be useful as cancer chemopreventive or chemotherapeutic agents. Limited in vitro studies indicate that several prenylated flavonoids present in the hop plant (Humulus lupulus) possess anticarcinogenic properties. The purpose of this study was to investigate the anti-tumorigenic effects of xanthohumol (XN), the major prenylflavonoid in hops, on prostate cancer and benign prostate hyperplasia. BPH-1 and PC3 cell lines were used in our study to represent both non-tumorigenic hyperplasia and malignant prostate cancer. In both BPH-1 and PC3 cells, XN and its oxidation product, XAL, decreased cell viability in a dose dependent manner (2.5-20 microM) as determined by MTT assay and caused an increase in the formation of early and late apoptotic cells as determined by Annexin V staining and multicaspase assays. XN and its oxygenated derivative also induced cell cycle changes in both cells lines, seen in an elevated sub G1 peak at 48h treatment. Western blot analysis was performed to confirm the activation of proapoptotic proteins, Bax and p53. XN and its derivative caused decreased activation of NFkappaB. This work suggests that XN and its oxidation product, XAL, may be potentially useful as a chemopreventive agent during prostate hyperplasia and prostate carcinogenesis, acting via induction of apoptosis and down-regulation of NFkappaB activation in BPH-1 cells.

Mol Nutr Food Res. 2005 Sep;49(9):874-81.

Enrichment of xanthohumol in the brewing process.

Wunderlich S, Zürcher A, Back W.

Lehrstuhl für Technologie der Brauerei I, TU München-Weihenstephan, Germany.

Xanthohumol (XN), a component of hops, is lost in significant quantities in the conventional brewing process. In commercial beers less than 0.2 mg XN/L are found. In order to increase the yield of XN in the brewing process, the parameters of XN recovery were studied. During wort boiling, XN is largely isomerised to isoxanthohumol. Further losses are owing to the precipitation and absorption of XN to yeast cells and haze particles and by filtration. The use of XN-enriched hop products combined with a late hop dosage during wort boiling proved to be effective in increasing the XN content in beer. The yield was further raised by a low-pitching rate and the abnegation of beer stabilisation. The use of dark malts had a positive effect on the XN recovery. Investigations of roasted malt extracts revealed several high-molecular substances that are able to form complexes with XN. These complexes proved to be stable in the brewing process. Depending on the addition of roasted malt or special XN-enriched roasted malt extracts, dark beers with more than 10 mg XN/L were achieved. Results obtained led to a brewing technology that produced on an industrial scale pale wheat beer with more than 1 mg XN/L.