Humulus lupulus / Hop

HUMULUS LUPULUS L. / Hop / gedeelte van de monografie uit het cursusboek herboristen opleiding 'Dodonaeus'

ALGEMENE EN BOTANISCHE INFORMATIE
  • Familie: Cannabinaceae - Hennepfamilie.
  • Verwante geslacht: Cannabis sativa
  • Naam: Houblon (Fr.), Hopfen (D.), Hops (E.).
  • Teelt, ecologie: Klimhemikrypt in alluviale bossen, voedselrijke elzenbossen, oevers van 
  • waterlopen, heggen. Tweehuizig.
  • Vermeerderen door scheuren van de wortels.
MATERIA MEDICA
Lupuli coni / strobuli, De kegels of kogelvruchten van de vrouwelijke bloeiwijzen van Humulus lupulus L.
  • Oogst: September
  • Drogen: Voorzichtig om het zgn. 'hopmeel' tussen de schubben van de rijpe kegelvruchten niet te verliezen.
  • Beschrijving: Lichtgeel, soms bruinachtig verkleurde uit schubblaadjes opgebouwde kogelvrucht.Tussen de schubben bevindt zich een geel, grofkorrelig poeder met aromatische, wat valeriaanachtige geur. Het laat zich moeilijk met water bevochtigen, door wrijving vormt zich een kneedbare massa.
  • Smaak: bitter aromatisch.
Lupuli glandulae De klierharen uit de vrouwelijke bloeiwijzen van Humulus lupulus L.
Bewaren: In goed gesloten vaten, buiten invloed van het licht, liefst maar 6 mnd. (?)

SAMENSTELLING
** E.o. 1-3 % (vooral in de klierharen) met: humulon (sesquiterpeen), myrceen, farnaseen, borneolvaleriaanesters worden door oxydatie omgezet tot valeriaanzuur (geur).
** Harsen 15-30 % (77 % in klierharen) met bitterstoffen: humulon, lupulon. Wordt bij bewaring omgezet in 2-methyl-3-buteen-2-ol.
** Hormonale stoffen: oestrogene en anti-androgene verbindingen (vooral in verse hop) Fyto-oestrogene isoflavonen: isoxanthohumol, 8-prenylnarigenine** werkt zoals oestradiol (DeKeukeleire)
* Looistoffen (humulotanninezuur)
* Mineralen o.a. veel kalium en Water 10 %

The major constituents are bitter substances (15–25%) in the resins. The resins are differentiated into hard (petroleum-ether insoluble) and soft resins. The lipophilic soft resins contain mainly α-acids (e.g. α-humulene (2,6,9-humulatriene) and related humulones) and ß-acids (lupulones). The major chemical constituents of the soft resins are humulone and lupulone and their related derivatives, 2–10% and 2–6%, respectively. The hard resin contains a hydrophilic fraction, δ-resin, and a lipophilic fraction, γ-resin. The essential oil (0.3–1.0%) contains mainly monoterpenes and sesquiterpenes such as ß-caryophyllene, farnesene, humulene and ß- myrcene (3, 5, 6, 11, 12). The essential oil also contains traces of 2- methylbut-3-ene-2-ol, which increases in amount to a maximum of 0.15% after storage of the strobiles for 2 years, owing to degradation of the humulones and lupulones. Other constituents include the chalcone xanthohumol, prenylflavonoids and other flavonoids (e.g. kaempferol, rutin) and tannins

Onderzoekers van de Universiteit Gent ontdekten in lupuline, het gele poeder in de hopbel, het krachtigste fyto-oestrogeen van de plantenwereld: hopeïne (8-prenylnaringenine). Fyto-oestrogenen zijn plantaardige stoffen die structurele gelijkenissen vertonen met de oestrogenen die in het vrouwelijk lichaam worden geproduceerd. De fytovarianten kunnen de werking van het vrouwelijke hormoon oestradiol nabootsen, en zo overgangsklachten verzachten. Het sterk op hopeïne gelijkende isoxanthohumol is verantwoordelijk voor de hormonale werking. Op zich is isoxanthohumol een biologisch inactieve stof, maar in de dikke darm zet de bacterie Eubacterium limosum het voor meer dan 80 procent om in werkzaam hopeïne. 


Hop en zijn medisch verleden
De klimplant Hop, Humulus lupulus hoort samen met Hennep tot de kleine plantenfamilie der Cannabaceae. Deze twee geslachten zijn niet alleen botanisch familie van mekaar, maar bezitten beide ook dezelfde sedatieve werking.
Het medicinale gebruik van hop wordt reeds in de Middeleeuwen beschreven, maar de speciale toepassing van de hopbellen (Lupuli strobulus) en de klierharen aan de schubben (Glandulae Lupuli) als sedativum en inslaapmiddel zijn van jongere datum.

Vroeger anders gebruikt.
In vroeg-middeleeuwse teksten wordt hop in de eerste plaats beschreven als een urinedrijvend, bloedzuiverend en menstruatiebevorderend middel. Reeds in de achtste eeuw prijst de Arabische arts Mesue hopsiroop aan als een goed middel bij galziekten en voor de zuivering van het bloed. Hop werd ook voorgeschreven door Paracelsus en wel tegen spijsverteringsstoornissen. In 'Den Herbarius in Dyetsche', een kruidenboek dat omstreeks 1500 in Antwerpen werd gedrukt en gebaseerd is op kruidenboeken uit het laatste kwart van de 15e eeuw, wordt hop genoemd als waardevol geneesmiddel tegen koorts, verstopping en leverziekten.' Het sap van het hoppekruid met kaaswei of met andijviewater, is goed tegen de geelzucht en ook tegen de hete lever'. Of ook nog ‘Het helpt om te ontlasten en om zijn behoefte te doen want het helpt de gaten te openen’. Bij Dodonaeus in zijn ‘Dertienste boeck. Over gheslachten van winde, klockskens ende dierghelijck ghewas schrijft hij over het hoppe-cruydt ‘zij doen het water rijsen ende verlichten den kamergangh wat’. In de latere uitgebreide uitgave van 1644 wordt wel al verwezen naar de nu bekende hormonale werking ‘ de bellen van de hoppe in de bad-stoven ghedaen als de vrouwen daer in zitten, zijn goedt om de ontstekinghen van de schamelijke leden der vrouwen te doen ghenesen...’

Hopkussen.
Ondanks dat in de meeste middeleeuwse literatuur de sedatieve werking van hop niet beschreven wordt, moeten we er toch van uit gaan, dat op zijn minst in de teeltgebieden die werking wel bekend moest zijn. Er wordt bijvoorbeeld vermeld dat de hoppluksters tijdens het werk uitzonderlijk vermoeid werden. En dat bij slaapstoornissen er een linnen zak met hop op of onder het hoofdkussen werd gelegd. De plant werd door Hufeland als amarum en zenuwmiddel geprezen. Pas bij Hecker vinden wij het therapeutische gebruik van hopbellen, waaraan hij de tonische werking van de bittermiddelen toeschrijft. Hij schrijft ook dat de bellen kalmerend werken op het zenuwstelsel, hoewel hij ze geen narcotische werking toekent. Pas in 1822 werd Hop in de Duitsland officieel als sedativum en licht hypnoticum erkend. Onafhankelijk van mekaar, heeft men ook in andere culturen de kalmerende werking van Hop ontdekt. Amerikaanse indianen gebruikte de plant bij slapeloosheid en als pijnstiller. Aan de andere kant van de aardbol werd in de Indiase Ayurveda Hop tegen rusteloosheid ingezet.

Andere toepassingen uit het verleden.
In Hongarije werden de hopbellen met liguster in wijn getrokken om tandpijn te stillen. Ook in Bohemen bestreden de mensen tandpijn door een holle kies met hopolie te vullen. Als zalf werd de hop ook bij huidziekten toegepast, zoals bij mensen die met ‘schorf, ruydigh, rappigh, pockigh ende met eenighe andere ghebreken aanden huyt ghequelt zijn’. Het sap werd ook in de oren gedrupt ‘reinight ende bevrijdt deselve van stanck ende oock van verrottinghe. Het moet daar in de Middeleeuwen nogal wat geweest zijn. Maar tegen tandpijn, oorpijn en huidziekten gebruiken we nu de hop niet meer.

Dr. Weiss en Humulus lupulus.
Dichter bij ons in tijd en afstand, beschrijft de vader van de moderne fytotherapie in Duitsland, R. F. Weiss, hop al in de eerste druk van zijn "Lehrbuch der Phytotherapie", destijds nog onder de titel "Die Pflanzenheilkunde in der arztlichen Praxis". Daarin schrijft hij: "Hop is een mild sedativum, maar kan zich niet meten met valeriaan. Daar staat tegenover dat deze plant enige bijzondere eigenschappen heeft. Hop geldt als bijzonder slaapbevorderend en zou verder een aanzienlijke werking uitoefenen op seksuele opwindingstoestanden. Verder heeft hop een stimulerende werking op de maag in de zin van een mild stomachicum, waarvoor de bitterstof verantwoordelijk is. Voor hop kunnen wij derhalve komen tot drie voorkeurgebieden van toepassing:
Seksuele neurosen, polluties, ejaculatio praecox, anafrodisiacum in het algemeen;
slapeloosheid en
nerveuze maagproblemen.
Derhalve zal hop op verschillende wijzen dienen te worden voorgeschreven". Vervolgens geeft hij enkele voorbeelden van verschillende recepten al naar gelang het toepassingsgebied. In latere drukken van zijn leerboek, wijst Weiss op het gehalte aan plantaardige hormonen die overeen zouden komen met oestrogenen, waardoor de dempende werking van hop op seksuele opwindingstoestanden bij mannen zou kunnen worden verklaard. Volgens Weiss is het eenvoudigste voorschrift een theemengsel van gelijke delen Strobuli Lupuli en Radix Valerianae. Een oud volksmiddel zou een slaapdrank van verse hopbellen zijn, of men stopte deze in een hoofdkussentje om de slaap te bevorderen. Ten slotte is het nog opmerkelijk, dat tot in de negentiende eeuw veel melding is gemaakt van de toepassing van hop bij pijnlijke erecties, zogenaamde priapismus.

Hedendaagse medische werking van Hop samengevat.
  • Bij slapeloosheid, vooral goed om inslapen te bevorderen met Valeriaan en Melisse
  • Voor de spijsvertering, bij nerveuze maagklachten met Melisse en Munt
  • Voor de overgang met Echte salie en Venkel


H. Kleijn (1970), Planten en hun naam
Húmulus | Húmulus lúpulus: Hop

De afleiding van de wetenschappelijke geslachtsnaam is nog allerminst zeker. We moeten het waarschijnlijk niet bij de Ouden zoeken, want zij schijnen de Hop niet te hebben gekend, hoewel Plinius spreekt van Lupulus salictarius (zie hieronder). Men veronderstelt dat de naam uit het Duits of Germaans is ontstaan en wel van humel of humela. Anderen menen dat de naam afkomstig is van humus: bodem, of humure: vochtig zijn, vanwege het groeien op vochtige plaatsen. Ook meent men dat de middeleeuwse naam van hümulus ontstaan zou kunnen zijn uit het Slavische chmeli, dat hop beduidt.
De naam Hop, in het Duits Hopfen, is afkomstig van het Oudduitse woord hopfo; zo neemt men aan. Bij Hildegard von Bingen (ca. 1150) treffen we de naam hoppho aan. Bij latere middeleeuwse Duitse schrijvers heet de plant Hoppen, zoals we bij Albertus Magnus (ca. 1250) kunnen lezen. De naam Hoppe schijnt van Germaanse oorsprong te zijn. Men wil het afleiden van het Duitse heben: opheffen, omdat de plant zich met haar windende stengel in de hoogte verheft. De naam Hupa bij Heukels, zonder enige nadere aanduiding, zal wel een verlatijnste naam zijn, want in het Middelnederlands treffen we huppe aan als naam voor de hop.
De soortnaam lupulus (verkleinwoord) komt van lupus: wolf, omdat de plant zich om wilgen, elzen en hakhout slingert en deze als het ware als een wolf wurgt. Dan wordt ons de naam bij Plinius ook duidelijk, namelijk Lupus salictarius: Wilgewolf, als tenminste met deze naam de hop werd bedoeld.
Hoewel het een Europese plant is van de gematigde zone, is zij volgens een Engels gezegde aldaar geen inheemse plant, want de hop werd pas onder Hendrik viii uit Vlaanderen of Nederland in Engeland ingevoerd. Het gezegde waarop we doelden luidt:
Hops and turkeys, mackerel and beer,
Came to England all in one year.
Een variant daarop luidt:
‘Hops, reformation, bays and beer,
Came to England all in one year.’
Reeds zeer vroeg moeten de hopbellen - dat zijn de tot vrucht gekomen vrouwelijke bloeiwijzen - bij het bereiden van bier gebruikt zijn. De hop geeft aan het bier een bittere smaak, maar maakt het ook houdbaarder, want het verhindert de ontwikkeling van de melkzuurbacteriën. Het valt echter op dat een drank die zulk een grote plaats onder de toenmalige bevolking innam, niet was opgenomen in de Capitulare de villis van 795 en andere geschriften van die tijd. Want in een aan de abdij van Sint Denis gerichte schenkingsbrief van Pepijn de Korte anno 786 is reeds sprake van een hopkwekerij (humlonaria).
Zo wordt in een oorkonde van de negende eeuw van het klooster Freisinger bij Meichelbech eveneens van een hopkwekerij gewag gemaakt. Via de kloosters werd de hop meer en meer aan het bier toegevoegd, in plaats van andere bitter smakende stoffen zoals eikeschors en de Gagel (Mýrica gále). Bij Hildegard von Bingen (ca. 1150) vinden we voor het eerst een schriftelijke mededeling dat deze plant bij het bier maken aangewend wordt. De bitter smakende aromatische stof die de hopbellen bevat, wordt gevormd door kleine kliertjes die zich alleen in de vrouwelijke bloemen bevinden, onderaan de schutblaadjes. Dit is ook de reden waarom men alleen vrouwelijke planten kweekt.
In de geneeskunde werden de hopbellen en het zaad gebruikt als urineafdrijvend middel, ter versterking van de maag, ter bevordering van de maanstonden enzovoort. Een hoofdkussen gevuld met hopbellen werd vroeger voorgeschreven als slaapverwekkend middel bij nerveuze slapeloosheid. In de Nederlandse Farmacopee treft men Hopklieren - Glandulae Lupili - aan, hetgeen er op wijst dat de hop nog als geneeskruid te boek staat. Trouwens de laatste jaren is men bezig de stof - lupuline - die door de kliertjes afgescheiden wordt, nader te onderzoeken. In het voorjaar gebruikte men de hopscheuten of hopsprietjes, dat zijn de bottende stengels, als een soort asperge, ook in ons land. Reeds in 1563 schrijft P. A. Matthiolus: ‘Im Frueling lassen die Leckmuelen (lekkerbekken) die jungen Hopfenspargen zum Salat bereyten.’ Minder bekend is dat vroeger de jonge spruiten als een soort groente werden gekweekt. Slaat men oude huishoudboeken of recepten uit de achttiende en de negentiende eeuw op, dan vindt men daar nog vele recepten in opgenomen om de jonge spruiten klaar te maken. In Vlaanderen zijn heden ten dage nog enkele kwekerijen die deze hopspruiten - Hopkeesten genaamd - voor de consumptie kweken.


Hop wetenschappelijk onderzoek: hormonaal

Hop (Humulus lupulus L.)
In 1999 publiceerde de onderzoeksgroep van prof. dr. Denis De Keukeleire van de Faculteit Farmaceutische Wetenschappen, Universiteit Gent, voor het eerst dat hop het sterkste fyto-oestrogeen in de natuur bevat, namelijk 8-prenylnaringenine, ook hopeïne genoemd, behorend tot de klasse van de polyfenolen, meer specifiek tot de subklasse van de prenylflavonoïden (7). Deze revelerende en intrigerende vinding werd inmiddels door 5 onafhankelijke onderzoeksgroepen uit Duitsland, Engeland en Japan bevestigd (8). Bovendien heeft een Japanse onderzoeksgroep gevonden dat hopeïne een krachtige werking bezit tegen botontkalking (9), terwijl aan een Frans onderzoekscentrum aangetoond werd dat hop warmte-opwellingen sterk reduceert (10). Hopeïne lijkt dus wel een 'wondermolecule' te zijn voor menopauzale vrouwen. Bovendien is er in hop nog een ander bestanddeel aanwezig, xanthohumol, dat, zoals hopeïne, behoort tot de groep van de prenylflavonoïden, doch, in tegenstelling tot hopeïne, geen oestrogene activiteit vertoont. Aan het Duitse Centrum voor Kankeronderzoek te Heidelberg werd de anti-kankerwerking van xanthohumol in detail bestudeerd in het kader van een omvangrijke studie, waarbij meer dan 2.000 plantaardige verbindingen onderzocht werden aan de hand van een 20-tal anti-kankertesten. Enkel xanthohumol was actief in alle testen, wat de uitzonderlijke waarde van deze hopverbinding illustreert. Xanthohumol vertoont een opmerkelijk breed spectrum van inhibitiemechanismen bij initiatie, promotie en progressie van kankers (11).
  
7. S. R. Milligan, J. C. Kalita, A. Heyerick, H. Rong, L. De Cooman, D. De Keukeleire. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. Journal of Clinical Endocrinology and Metabolism 84:2249-2252 (1999). Vervolgpublicaties: R. S. Milligan, J. C. Kalita, V. Pocock, V. Van de Kauter, J. F. Stevens, M. L. Deinzer, H. Rong, D. De Keukeleire. The endocrine activities of 8-prenylnaringenin and related hop (Humulus lupulus L.) flavonoids. Journal of Clinical Endocrinology and Metabolism 85:4912-4915 (2000). S. R. Milligan, J. C. Kalita, V. Pocock, A. Heyerick, L. De Cooman, H. Rong, D. De Keukeleire. Oestrogenic activity of the hop phyto-oestrogen, 8- prenylnaringenin. Reproduction 123: 235-242 (2002).
   8. N. G. Coldham, M. J. Sauer. Food and Chemical Toxicology 39:1211-1224 (2001). S. Gester et al. Tetrahedron 57:1015-1018 (2001). O. Zierau et al. Planta Medica 68:449-451 (2002). O. Schaefer et al. Journal of Steroid Biochemistry and Molecular Biology 84:359-360 (2003). T. Takamura-Enya et al. Food and Chemical Toxicology 41:543-550 (2003).
   9. M. Miyamoto, Y. Matsushita, A. Kikokawa, C. Fukuda, Y. Iijima, M. Sugano, T. Akiyama. Estrogenic effects of 8-isopentenylnaringenin on bone metabolism, Planta Medica 64: 769-769 (1998).
  10. P. Goetz, Traitement des bouffées de chaleur par insuffisance ovarienne par l'extrait de houblon (Humulus lupulus). Revue de Phytothérapie Pratique (4):13-15 (1990).
  11. C. Gerhauser, A. Alt, E. Heiss, A. Gamal-Eldeen, K. Klimo, J. Knauft, I. Neumann, H. R. Scherf, N. Frank, H. Bartsch, H. Becker. Cancer chemopreventive activity of xanthohumol, a natural product derived from hop. Molecular Cancer Therapeutics 1: 959-969 (2002). 



Humulus lupulus monograph

English Common Names
Hop, common hop, English hop, European hop.
"Hop" refers to a hop plant; "hops" refers to the hops of commerce, i.e., the female cones.

French Common Names
Houblon.

Morphology
Hop is a high-climbing, wind-pollinated, perennial vine, sometimes extending more than 10 m. The vines climb by twining, and are assisted in holding onto surfaces by two-hooked hairs that resemble miniature grappling hooks. The annual, above-ground stem is killed by frost each year, re-growth occurring each season from perennial underground rhizomes and from buds on the rootstock (crown). The rootstocks can live for half a century. The perennial crown becomes woody with age, with heavy, rough, dark brown bark. The hop plant is propagated primarily vegetatively rather than by seeds. More than one hundred cultivars have been named, each essentially a clone. Many of these are of hybrid origin, and have been reproduced asexually for centuries. Some plants have male flowers, others have female flowers; occasionally plants bear both kinds. In most natural populations of hop, female plants are about twice as numerous as males. Because the female plants produce the commercially valuable hops (the cones or fruit-clusters), and also are of greater ornamental value than the males, the latter are generally discarded as soon as they can be recognized. However, a few males are usually planted deliberately in England because they increase yield and it is not economical to grow most English cultivars seedless. Male flowers are not organized into "cones," but are in loose inflorescences (panicles). In most hop plantations, males are regarded as a nuisance, since their pollen fertilizes the females, and prevents the formation of the valuable "seedless hops" that are predominantly preferred in commerce. A resin with the valuable brewing constituents is produced in yellow glands on the bracteoles of the cone, as well as on the seeds.

Classification and Geography
Humulus has three species, indigenous in north-temperate areas. Only the perennial H. lupulus is native to North America. The Asian annual H. japonicus Sieb. & Zucc. is a naturalized weed of eastern North America, including southern Ontario and southwestern Quebec.
There are five varieties of H. lupulus: var. lupulus of Eurasia; var. cordifolius (Miquel) Maximowicz of Japan; var. neomexicanus Nelson & Cockerell, the predominant wild hop in the western Cordillera of North America, found from Mexico to British Columbia; var. pubescens E. Small, of the midwestern US; and var. lupuloides E. Small, of eastern North America, which includes most wild hops from the Prairie Provinces to the maritime provinces. The distribution of the two indigenous Canadian varieties is shown on the map. In much of Canada and the US the European var. lupulus is found as an escaped plant from past use in brewing, or as a persisting ornamental around abandoned homesteads. Variety lupulus is the ancestor of most brewing cultivars used today. However, both in Japan and in North America, the local wild hops hybridized with the imported European hop to produce unique cultivars.
  
Ecology
Hop plants frequently occur in moist thickets, slopes, river banks, alluvial woods, or along fences and hedges, often in sandy soils. The plants grow best in rich, alluvial soils, and typically occur in sandy or gravelly loams. Well-drained soils are especially beneficial in areas subject to frost heaving of the roots. Hop is adapted to a wide range of temperate climates. Although it is quite tolerant of low temperatures, good snow cover can reduce winterkill in very cold regions. Hop is somewhat shade tolerant, but prefers full sun.

Medicinal Uses
The high oil and resin content of hops contributed to a reputation, greatly exaggerated, for valuable medicinal properties, and hops have a long history of use in folk medicine. Hop resin is bacteriostatic (against gram-positive organisms) and this factor may lend some credibility to use of hop in former times for treatment of certain types of epidermal sores and irritations, and bacterial infections such as tuberculosis. The hop plant is related to the hemp (marihuana) plant, tempting some to try to smoke the leaves. However, hops are devoid of the mood-altering chemicals found in marihuana. Today, hop extract is used as an aromatic bitter principle in pharmaceutical preparations and in shampoos. Extracts are used in skin creams and lotions in Europe for their alleged skin-softening properties.
There is a long Eurasian tradition of using hops to induce sleep, including putting the cones in pillows, and planting hop beside bedrooms. Remarkably, American Indians independently adopted the soporific use of the plant. The tranquillizing effect commonly alleged in folklore for hops may have a logical basis in a sedative volatile alcohol, dimethylvinyl carbinol, which comprises up to 0.15% of the dried leaves.

Toxicity
Hop plants are not considered toxic, although they have caused dermatitis in as many as one in 30 hop workers.

Chemistry
The commercial value of hops is due to resins which give beer its bitterness, and essential oils which contribute to flavor and aroma. Tannins are also present, which give astringency to preparations made with hops. Over 200 essential oil constituents have been identified, chiefly myrcene, humulene, and caryophyllene, with minor amounts of dipentene, linalool, farnesene and methyl nonyl ketone. The important brewing resins include alpha-acids (a-acids) and the beta-acids (b-acids), also referred to as humulones and lupulones, respectively. Both contribute bitterness to beer, but the a-acids are much more intense than the betha-acids. The alpha-acids are a mixture of chemical analogues, including humulone, cohumulone, and adhumulone; similarly the b-acids are a mixture of lupulone, colupulone, and adlupulone. Brewers have long recognized that North American cultivars have a higher content of alpha acids and produce beer of stronger aroma. Bitter hops are very important commercially, and nearly all owe a great deal to American germplasm. Content of a-acid varies from about 3.5% in traditional European types to as much as 15% in newer bitter varieties. The European forms of hop have a relatively low content of "soft resins" (a- and b-acids collectively), a ratio of a:b approaching one, low cohumulone, moderately low essential oil content, and relatively low myrcene in the essential oil fraction. Native American hop plants are quite high in cohumulone and colupulone content, and have a pungent, unpleasant aroma.

Non-medicinal Uses
Hop has been used through recorded history for various culinary and household purposes, although it is chiefly known as a brewing ingredient. Hop extracts and oil have been used to flavor tobacco, yeast, beverages other than beers, frozen dairy desserts, candy, gelatins, puddings, baked goods, various confections, chewing gums, and condiments. In the past, yeast for bread-making was prepared by culturing wild yeast in a decoction of hops and water. The hops added flavor and apparently prevented the yeast from spoiling by virtue of their antiseptic properties.

Agricultural and Commercial Aspects
The cultivation of hop was not introduced into England until the close of the 15th century. The hop was brought to North America and grown in the early 17th century. The first commercial brewery in Canada was founded in Quebec about 1668 by the Intendant Jean Talon, to control the intemperate use of stronger drink. By the middle of the 19th century, New England and New York produced the bulk of the hops of the New World. However, by the early 20th century, the Pacific Coast became the leading hop-producing area in North America. In the 1920's hop growing in New York was practically wiped out by downy mildew and by Prohibition. Similarly, in eastern Canada commercial hop growing was phased out by the end of the Second World War, but became established in British Columbia.
About two dozen countries, including Canada, raise substantial commercial crops of hops. Germany is the largest producer, followed by the US. Other centers of hop production include Russia, China, England, the former Czechoslovakia, and the former Yugoslavia. About 114,000 tonnes are produced worldwide annually, on more than 90 000 ha.
Hop is a good example of a crop that has been substantially improved recently through incorporation of wild germplasm. A wild hop from Manitoba contributed to the improvement of many standard brewing varieties. Indeed, the improved cultivars account for an ever-increasing proportion of production. The contribution of wild hop germplasm was recently valued at almost $90,000,000 annually in North America.
The use of hop shoots as a vegetable is an interesting possibility. Young shoots (6-10 cm long) are often consumed as a pot-herb, like asparagus. These spears can be boiled for 2-3 min, and then boiled in a change of water until tender. When steamed for 5 min and served with melted butter or cheese sauce, the shoots taste much like asparagus. In hop-producing areas of Europe, blanched hop spears are often served in fine restaurants. Hop farmers generally have surplus rhizomes from which the spears can be harvested, but because of their desire to maintain possession of unique hop strains, they may not be willing to sell them. In any event, there is a need to select strains that produce tasty shoots rather than good brews.
Given the substantial cultivation and availability of hop for food and flavoring purposes, growing the plant specifically as a pharmaceutical crop seems unwarranted.

Myths, Legends, Tales, Folklore, and Interesting Facts
St. Hildegard (1098-1179, also known as Hildegard of Bingen and Hildegardis de Pinguia), was an abbess who established a convent and a Benedictine nunnery near the Rhine River. She was one of the most remarkable women the world has ever known, becoming an adviser to popes, kings, and various dignitaries. She wrote on nature and medicine, and was a mystical and spiritual visionary who interpreted Oriental, Judeo-Christian and Greek philosophy. St. Hildegard is often credited with being the first person to popularize the use of hops in brewing.
In England about 1500, after learning of how well hops preserved beer in continental Europe, British brewers started adding hops to ale (sweet beer made without hops), turning it into bitter beer. Henry VIII (1491-1547), responding to a petition to ban hop, described as "a wicked weed that would endanger the people," outlawed the use of hop by brewers. His son, Edward VI (1537-1553), rescinded the ban in 1552.
Charles Darwin entertained himself while sick in bed in 1882 by studying a hop plant growing on his window-sill. He noted that the tip of the stem completed a revolution in 2 hours.
The patent office of the US once granted a patent to a man who claimed to have "invented" the hop's habit of winding from left to right (i.e., circling clockwise, viewed so that the twining stem is growing towards the observer).

Selected References
Barth, H.J., Klinke, C., and Schmidt, C. 1994. The hop atlas - the history and geography of the cultivated plant. Joh. Barth & Sohn, Nurenberg, Germany. 383 pp.
Brady, J.L., Scott., N.S., and Thomas, M.R. 1996. DNA typing of hops (Humulus lupulus) through application of RAPD and microsatellite marker sequences converted to sequence tagged sites (STS). Euphytica 91: 277-284.
Bravo, L., Cabo, J., Fraile, A., Jimenez, J., and Villar, A. 1974. Pharmacodynamic study of the lupulus (Humulus lupulus L.) tranquilizing action. Boll. Chim. Farm. 113: 310-315. [In Spanish.]
De Keukeleire, D., Milligan., S.R., De Cooman, L., and Heyerick, A. 1997. The oestrogenic activity of hops (Humulus lupulus L.) Pharmaceut. Pharmacol. Lett. 7(2-3): 83-86.
Eckel, A., and Fritz, D. 1990. Forcing of hop shoots as a vegetable. 1. Comparison of various hop cultivars. Gartenbauwissenschaft 55: 34-36. [In German.]
Eckel, A., and Fritz, D. 1990. Forcing hop shoots (Humulus lupulus L.) as a vegetable: II. Comparison of different propagation methods and set sizes. Gartenbauwissenschaft 55(2): 90-92. [In German.]
Edwardson, J.R. 1952. Hops - their botany, history, production and utilization. Econ. Bot. 6: 160-175.
Guelz, P.G., Mueller, E., Herrmann, T., and Loesel, P. 1993. Epicuticular leaf waxes of the hop (Humulus lupulus). Chemical composition and surface structures. Z. Naturforsch. Sect. C, Biosci. 48: 689-696.
Hampton, R.O. 1988. Health status (virus) of native north American Humulus lupulus in the natural habitat. J. Phytopathol. (Berlin) 123: 353-361.
Haunold, A. 1993. Agronomic and quality characteristics of native North American hops. Am. Soc. Brew. Chem. J. 51: 133-137.
Katsiotis, S.T., Langezaal, C.R., and Scheffer, J.J.C. 1990. Composition of the essential oils from leaves of various Humulus lupulus L. cultivars. Flavour Fragrance J. 5(2): 97-100.
Katsiotis, S.T., Langezaal, C.R., Scheffer, J.J.C., and Verpoorte, R. 1989. Comparative study of the essential oils from hops of various Humulus lupulus L. cultivars. Flavour Fragrance J. 4(4): 187-192.
Kral, D., Zupanec, J., Vasilj, D., Kralj, S., and Psenicnik, J. 1991. Variability of essential oils of hops, Humulus lupulus L. J. Inst. Brewing 97: 197-206.
Langezaal, C.R., Chandra, A., and Scheffer, J.J. 1992. Antimicrobial screening of essential oils and extracts of some Humulus lupulus L. cultivars. Pharm. Weekbl. Sci. 14: 353-356.
Miller, N.G. 1970. The genera of the Cannabaceae in the southeastern United States. J. Arnold Arbor. 51: 185-203.
Mizobuchi, S., and Sato, Y. 1985. Antifungal activities of hop (Humulus lupulus) bitter resins and related compounds. Agric. Biol. Chem. 49: 399-404.
Munro, D.B., and Small, E. 1997. Vegetables of Canada. NRC Research Press, Ottawa, ON. 417 pp. [Chapter on Humulus: pages 219-225.]
Neve, R.A. 1991. Hops. Chapman and Hall, London, U.K. 266 pp.
Oliveira, A.M.M., and Pais, M.S. 1988. Glandular trichomes of Humulus lupulus cultivar Brewer's Gold: Ontogeny and histochemical characterization of the secretion. Nord. J. Bot. 8: 349-359.
Oliveira, A.M.M., and Pais, M.S. 1990. Glandular trichomes of Humulus lupulus cultivar Brewer's Gold (hops): ultrastructural aspects of peltate trichomes. J. Submiscrosc. Cytol. Pathol. 22: 241-248.
Parker, J.S., and Clark, M.S. 1991. Dosage sex-chromosome systems in plants. Plant Sci. (Limerick) 80: 79-92.
Pillay, M., and Kenny, S.T. 1994. Chloroplast DNA differences between cultivated hop, Humulus lupulus and the related species H. japonicus. Theor. Appl. Genet. 89: 372-378.
Pillay, M., and Kenny, S.T. 1996. Structure and inheritance of ribosomal DNA variants in cultivated and wild hop, Humulus lupulus L. Theor. Appl. Genet. 93: 333-340.
Polley, A., Seigner, E., and Ganal, M.W. 1997. Identification of sex in hop (Humulus lupulus) using molecular markers. Genome 40: 357-361.
Simpson, W.J., and Smith, A.R.W. 1992. Factors affecting antibacterial activity of hop compounds and their derivatives. J. Appl. Bacteriol. 72: 327-334.
Small, E. 1978. A numerical and nomenclatural analysis of morpho-geographic taxa of Humulus. Syst. Bot. 3: 37-76.
Small, E. 1980. The relationships of hop cultivars and wild variants of Humulus lupulus. Can. J. Bot. 58: 676-686.
Small, E. 1981. A numerical analysis of morpho-geographic groups of cultivars of Humulus lupulus L. based on samples of hops. Can. J. Bot. 59: 311-324.
Small, E. 1997. Cannabaceae. In Flora of North America, north of Mexico, vol. 3. Edited by Flora North America Editorial Committee. Oxford University Press, New York, NY. pp. 381-387.
Small, E. 1997. Culinary Herbs. NRC Research Press, Ottawa, ON. 710 pp. [Chapter on Humulus: pages 283-289.]
Stevens, R. 1967. The chemistry of hop constituents. Chem. Rev. 67: 19-71.
Suominen, J. 1994. The northernmost finds in the world of native Humulus lupulus. Aquilo Ser Bot. 33: 121-129. [In Finnish.]
Takahashi, T., Ohsawa, M., Shimakoshi, S., Kishi, H., Kawahara, M., and Yoshikawa, N. 1993. Development cytology of the resin glands of hop (Humulus lupulus L.). J. Hortic. Sci. 68: 797-801.
Tsuchiya,Y., Araki, S., Takashio, M., and Tamaki, T. 1997. Identification of hop varieties using specific primers derived from RAPD markers. J. Ferment. Bioeng. 84(2) : 103-107.
Whittington, G., and Gordon, A.D. 1987. The differentiation of the pollen of Cannabis sativa L. from that of Humulus lupulus L. Pollen Spores 29: 111-120.
Yamanaka, T. 1994. Humulus lupulus var. cordifolius found in Shikoku. J. Jpn. Bot. 69: 179 [In Japanese.]



Newall, Carol A.; Anderson, Linda A. and Phillipson, J. David: Herbal Medicines - a guide for health-care professionals. London. The Pharmaceutical Press. 1996

Pharmacological Actions Hops

Animal studies 
Anti-bacterial activity, mainly towards Gram-positive bacteria, has beendocumented for hops and attributed to the humulone and lupulone constituents. The activityof the bitter acids towards Gram-positive bacteria is thought to involve primary membrane leakage. Resistance of Gram-negative bacteria to the resin acids is attributed to the presence of a phospholipid-containing outer membrane, as lupulone and humulone are inactivated by serum phospholipids. Structure activity studies have indicated the requirement of hydrophobic molecule and a six-membered central ring for such activity. The humulones and lupulones are thought to possess little activity towards fungi or yeasts.
However, antifungal activity has been documented for the bitter acids towards Trichophyton,Candida, Fusarium and Mucor species, and anti-bacterial activity towards Staphylococcus aureus.

Anti-spasmodic activity has been documented for an alcoholic hop extract on various isolated smooth muscle preparations. Hops have been reported to exhibit hypnotic and sedative properties. 2-Methyl-3-buten-2-ol, a bitter acid degradation product, has been identified as a
sedative principle in hops. 2-Methyl-3-buten-2-ol has been shown to possess narcotic properties in mice and motility depressant activity in rats, with the latter not attributable to a muscle-relaxant effect. It has also been suggested that isovaleric acid residues present in hops may contribute towards the sedative action.
Hops have previously been reported to possess oestrogenic constituents. However, when a number of purified components, including the volatile oil, and the bitter acids, were examined using the uterine weight assay in immature female mice, no oestrogenic activity was found. 

Human studies The documented human studies generally refer to hops given in combination with one or more additional herbs. Hops have been reported to improve sleep disturbances when given in combination with valerian. It has been stated that only low amounts of 2- methyl-3-buten-2-ol, the sedative principle identified in hops, are present in sedative tablets containing hops. However, it is thought that 2-methyl-3-buten-2-ol is formed in vivo by metabolism of the α-bitter acids, and therefore, the low amount of 2-methyl-3-buten-2-ol in a preparation may not indicate low sedative activity. Interestingly, relatively high concentrations of 2-methyl-3-buten-2-ol were found in bath preparations, suggesting that
high concentrations of 2-methyl-3-buten-2-ol may be achieved in both tea and bath products
containing hops.
Hops, in combination with chicory and peppermint, have also been documented to relievepain in patients with chronic cholecystitis (calculous and non-calculous). A herbal productcontaining a mixture of plant extracts, including hops and uva-ursi, and alpha tocopherolacetate has improved irritable bladder and urinary incontinence. Excellent results werereported for 772 out of 915 patients.

Side-effects, Toxicity
Respiratory allergy caused by the handling of hop cones have been documented; a subsequent patch test used dried, crushed flower heads proved negative. Positive patch test reactions have been documented for fresh hop oil, humulone, and lupulone. Myrcene, present in the fresh oil but read ily  oxidised, was concluded to be the sensitising agent in the hop oil. Contact dermatitis to hops has long been recognised and is attributed to the pollen. Small doses of hops are stated to be non-toxic. Large doses administered to animals by injection have resulted in a soporific effect followed by death, with chronic administrationresulting in weight loss before death.

Contra-indications, Warnings
It has been stated that hops should not be taken by individuals suffering from depressive illness, as the sedative effect may accentuate symptoms. The sedative action may potentiate the effects of existing sedative therapy and alcohol. Allergic reactions have been reported for hops, although only following external contact with the herb and oil.
Pregnancy and lactation In vitro anti-spasmodic activity on the uterus has been documented. In view of this and the lack of toxicity data, the excessive use of hops during pregnancy and lactation should be avoided.



Hops are the female inflorescences of the plant Humulus lupulus L. They are used primarily in beer brewing to add bitterness and flavor. Hops is also used as an herbal medicine for mood disturbance and insomnia (1) and to treat menopausal symptoms. In vitro studies have shown that hops has chemopreventive (2), (3), (4) antitumor (5), antiangiogenic (6), anti-inflammatory (19) and antidiabetic (7) properties. Hops also reduces hyperlipidemia (8) and obesity (9) in mice.

In human studies, a hops-valerian combination product improved sleep quality (10) (16), and insulin sensitivity in patients with type-2 diabetes (7). Data from an observational study suggest benefits of a combination of hops, rosemary extract and oleanolic acid in reducing arthritic pain (11). However, it is not clear whether hops alone would exert similar effects.

A hops extract was shown to alleviate menopausal symptoms (13) (17), and may improve bone health (18) in postmenopausal women. Some studies also indicate that derivates of hops have phytoestrogenic effects (7) (12). Until more research is done, patients with hormone-sensitive cancers should avoid it.

Mechanism of Action
Isomerized hops extracts (IHEs) increase plasma HDL levels and decrease atherosclerosis index (AI) in mice on high fat, high cholesterol diet via PPAR-alpha activation (14). These extracts also reduced plasma triglyceride levels and induced hepatomegaly (8). Other studies show IHE rich in isohumulone can inhibit PGE2 production and reduce the formation aberrant crypt foci in the colon of mice. Xanthohumol, a flavonoid from hop exhibits antiangiogenic effect by inhibiting the NF-kB and Akt pathway (6). A product containing hops extract reduces levels of C-reactive protein in patients with inflammatory diseases (12).

Prenyl flavonoids from hops, xanthohumol, isoxanthohumol, and 8-prenylnaringen (8-PN) inhibit aromatase activity and breast cancer cell proliferation, and increase breast cancer cell apoptosis in vitro (5). They also inhibit prostate cancer cell proliferation in vitro (3). However, isoxanthohumols are converted in the distal human gut into the phytoestrogen 8-prenylnaringen (8-PN) via the action of intestinal microflora (12). This process also occurs in the liver and is regulated by the cytochrome P450 enzymes (15).

Contraindications
Patients with hormone-sensitive cancer should avoid hops extracts due to their phytoestrogenic effects (7) (12).

Herb-Drug Interactions
Cytochrome P450 substrates:  Drugs that induce CYP1A2 may increase the estrogenic effect of hops extracts (15).
Paracetamol: Some hops species may slow clearance of paracetamol, thereby increasing its analgesic effects  (20).
  1. Piersen CE. Phytoestrogens in botanical dietary supplements: implications for cancer. Integr Cancer Ther. Jun 2003;2(2):120-138.
  2. Dietz BM, Kang YH, Liu G, et al. Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase. Chem Res Toxicol. Aug 2005;18(8):1296-1305.
  3. Delmulle L, Bellahcene A, Dhooge W, et al. Anti-proliferative properties of prenylated flavonoids from hops (Humulus lupulus L.) in human prostate cancer cell lines. Phytomedicine. Nov 2006;13(9-10):732-734.
  4. Nozawa H, Nakao W, Zhao F, Kondo K. Dietary supplement of isohumulones inhibits the formation of aberrant crypt foci with a concomitant decrease in prostaglandin E2 level in rat colon. Mol Nutr Food Res. Aug 2005;49(8):772-778.
  5. Monteiro R, Faria A, Azevedo I, Calhau C. Modulation of breast cancer cell survival by aromatase inhibiting hop (Humulus lupulus L.) flavonoids. J Steroid Biochem Mol Biol. Jun-Jul 2007;105(1-5):124-130.
  6. Albini A, Dell’Eva R, Vene R, et al. Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF-kappaB and Akt as targets. FASEB J. Mar 2006;20(3):527-529.
  7. Yajima H, Ikeshima E, Shiraki M, et al. Isohumulones, bitter acids derived from hops, activate both peroxisome proliferator-activated receptor alpha and gamma and reduce insulin resistance. J Biol Chem. Aug 6 2004;279(32):33456-33462.
  8. Shimura M, Hasumi A, Minato T, et al. Isohumulones modulate blood lipid status through the activation of PPAR alpha. Biochim Biophys Acta. Sep 5 2005;1736(1):51-60.
  9. Yajima H, Noguchi T, Ikeshima E, et al. Prevention of diet-induced obesity by dietary isomerized hop extract containing isohumulones, in rodents. Int J Obes (Lond). Aug 2005;29(8):991-997.
  10. Morin CM, Koetter U, Bastien C, Ware JC, Wooten V. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial.Sleep. Nov 1 2005;28(11):1465-1471.
  11. Lukaczer D, Darland G, Tripp M, et al. A pilot trial evaluating Meta050, a proprietary combination of reduced iso-alpha acids, rosemary extract and oleanolic acid in patients with arthritis and fibromyalgia. Phytother Res. Oct 2005;19(10):864-869.
  12. Possemiers S, Bolca S, Grootaert C, et al. The prenylflavonoid isoxanthohumol from hops (Humulus lupulus L.) is activated into the potent phytoestrogen 8-prenylnaringenin in vitro and in the human intestine. J Nutr. Jul 2006;136(7):1862-1867.
  13. Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. May 20 2006;54(2):164-175.
  14. Miura Y, Hosono M, Oyamada C, Odai H, Oikawa S, Kondo K. Dietary isohumulones, the bitter components of beer, raise plasma HDL-cholesterol levels and reduce liver cholesterol and triacylglycerol contents similar to PPARalpha activations in C57BL/6 mice. Br J Nutr. Apr 2005;93(4):559-567.
  15. Guo J, Nikolic D, Chadwick LR, Pauli GF, van Breemen RB. Identification of human hepatic cytochrome P450 enzymes involved in the metabolism of 8-prenylnaringenin and isoxanthohumol from hops (Humulus lupulus L.). Drug Metab Dispos. Jul 2006;34(7):1152-1159.
  16. Dimpfel W, Suter A. Sleep improving effects of a single dose administration of a valerian/hops fluid extract - a double blind, randomized, placebo-controlled sleep-EEG study in a parallel design using electrohypnograms. Eur J Med Res. 2008 May 26;13(5):200-4.
  17. Erkkola R, Vervarcke S, Vansteelandt S, et al. A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts.Phytomedicine. 2010 May;17(6):389-96.
  18. Holick MF, Lamb JJ, Lerman RH,et al. Hop rho iso-alpha acids, berberine, vitamin D3 and vitamin K1 favorably impact biomarkers of bone turnover in postmenopausal women in a 14-week trial. J Bone Miner Metab. 2010 May;28(3):342-50.
  19. Akazawa H, Kohno H, Tokuda H, et al. Anti-inflammatory and anti-tumor-promoting effects of 5-deprenyllupulonol C and other compounds from Hop (Humulus lupulus L.). Chem Biodivers. 2012 Jun;9(6):1045-54.
  20. Jakovljevic V, Popovic M, Raskovic A, et al. Effect of aroma and magnum hops extracts and paracetamol on antioxidant liver parameters in mice. Eur J Drug Metab Pharmacokinet. 2009 Jan-Mar;34(1):37-41.


Uit EMEA monograph 2008 over Humulus lupulus

Herbal substance    This assessment report reviews the available scientific data, particularly the pharmacological and  clinical studies available for Humulus lupulus L., strobiles (Cannabaceae) or hops.  The dried, generally whole female inflorescences of hops (Lupuli flores) are described in the European  Pharmacopoeia (Lupuli flos 01/2005:1222) (2005). They are also described in an ESCOP monograph  in 2003 with a therapeutic indication similar to valerian root viz. tenseness, restlessness and sleep  disorders. Hops are referred to in the herbal literature as having various forms of sedative activity  (Chadwick et al., 2006 and references cited therein namely Fluckiger and Hanbury, 1879, Maisch,  1892, Schleif and Galludet, 1907, Greenish, 1909, Wilcox, 1912, Culbreth, 1927, Washburn and  Blome, 1927, Gathercoal and Wirth, 1936, Youngken, 1950, Meyer, 1960, Millspaugh, 1974,  Blumenthal, 2000). They are often combined with more potent sedative herbs such as valerian, passion  flower and lemon balm for the treatment of sleep disturbances (Blumenthal 2000, Schultz et al., 2001).    

More than 99% of the world production of hops is intended for breweries, however, since 1973 it has  been claimed that brewing sludge baths containing ca. 30% hop extracts could be used for the  treatment of a variety of gynaecological disorders (Fenselau and Talahay, 1973). References to the  traditional use of hops in the treatment of such disorders have been identified from the US (Donsback,  1977), Romania (Racz et al., 1980), France (Goetz, 1990) and Iran (Zagari, 1992). Additionally, a  number of journal articles (Bednar and Zenisek, 1961, Strenkovskaya, 1968, Fenselau and Talahay,  1973) and patents exist concerning the use of oestrogenic properties of hops, particularly for external  use in cosmetics. Koch and Heim (1953), following up on the folk legend “that women who normally  live a distance from hop gardens regularly begin to menstruate 2 days after arriving to pick hops”,  reported that hops contain the equivalent of 20-300 µg oestradiol/g. While lacking in detail, this one- page article is apparently the first confirmation that hops may have oestrogenic activity in humans.  Koch and Heim used a version of the Doisy test, an in vivo assay with castrated female infant rodents  (Hensyl, 1990). Chury (1961) reported that the oestrogenic activity for a saponified ethanol extract of  hops was much more active than those of peas, red clover, and cabbage. Several hop-containing  cosmetic preparations have been patented since that time.     

It was not until 1988 that the chemical structure of the oestrogenic principle was established (Hänsel  and Schulz, 1988). The report by Milligan et al. (1999), however, may be regarded as the beginning of  the modern, unambiguous understanding of the in vitro oestrogenic activity of hops. They reported  that hops contain a very potent phyto-oestrogen, 8-prenylnaringenin (8-PN), also called hopein, which  belongs to the class of the prenylflavonoids. This finding has been confirmed by a number of  independent research groups, both by in vivo and in vitro studies (Coldham and Sauer, 2001, Zierau et  al., 2002,  Takamura-Enya et al., 2003). The high oestrogenic activity of 8-PN was reported for the  first time in 1998, when the compound was isolated from the heartwood of the tropical tree  Anaxagerea benzonensis A. Gray (Annonaceae) (Kitaoka et al., 1998). 8-PN has also been detected in  some beers, in relatively small quantities, however (levels between 20 µg – 100 µg/L) (Rong et al.,  2000, Schaefer et al., 2003). Since then several review articles on the oestrogenic properties of hops in  comparison to other phyto-oestrogens have been published (Cos et al., 2003, Ososki and Kenelly,  2003).  Hop extracts and/or compounds have also been reported to be active as antioxidants, cancer  chemopreventives, antiinflammatory agents, antimicrobials (antibacterials and antifungals), and  cytotoxics (Chadwick et al., 2006). These indications, however, are substantiated mainly by  pharmacological data and not by clinical studies.   

 Herbal preparations    The dried inflorescences are used in comminuted form as such or in tea mixtures or they are prepared  as infusions.  Lipophilic extracts are used for the preparation of bath oils whereas hydroalcoholic liquid extracts and  tinctures are prepared for internal use as sedatives, mostly in combinations with other sedative plant  extracts. In several cases, the hydroalcoholic liquid extracts are prepared with sweet wine.  Hop strobiles are described in the DAB10, PFX and the BHP. In the latter (1983) a liquid extract (1:1)  in 45% alcohol and a tincture (1:5) in 60% alcohol are given together with their posology. 

    German E Commission describes a monograph on hop strobiles and hop extracts as sedative in 1984  (BAnz nr. 228, dated 05.12.1984).    In Germany marketing authorisations were granted for HMPs containing:  •   Fluid extract (1:12.4-12.6) : ethanol 16% m/m (since 1965)  Daily dosage corresponding to 0.8 g herbal substance (HS) (in divided single dosages, 2-3 x daily)  •   Fluid extract (1:94-95), sweet wine (since 1978)  Daily dosage corresponding to 0.4-0.6 g HS (in divided single dosages, 2-3 x daily)  •   Fluid extract (1:10), sweet wine (since 1978)  Daily dosage corresponding to approximately 5 g HS (in divided single dosages, 2-3 x daily)  •   Dry extract (4-5:1), methanol 50% v/v (since 1993)  Daily dosage corresponding to 1-1.7 g HS (in divided single dosages, 2-3 x daily)   

 In Germany, the herbal substance is part of many combination products with Valerian, Passion flower  and Melissa in solid and liquid pharmaceutical forms.  Consequently, only hydroalcoholic liquid extracts among them wine and tinctures can be accepted as  traditional drugs.   
 
Assessor’s comments   
 ♦   References concerning the traditional medicinal use of hops as a sedative herb date back to 1879  (Fluckiger and Hanbury). Since then many publications up to the present day have appeared in  which hop strobiles as comminuted herbal substance, alone or in tea mixtures or as infusions  continue to be recommended by proponents of herbal medicine for this indication. Unfortunately,  despite numerous attempts the constituents responsible for the sedative effects of hops have yet to  be established, although some information about the biochemical mode of action of hops as  sedative herb is now available.  Besides the dried inflorescences only liquid extracts prepared with ethanol/water (16% and 45%) and  sweet wine, and tinctures (1:5) prepared with ethanol/water 60% have been used in medicinal products  for more than 30 years. Although the fluid extracts (1:12.4-12.6) and (1:94-95), prepared with ethanol  16% m/m and sweet wine, respectively, have been marketed in Germany since 1978, their daily  dosages corresponding respectively with 0.8 g and 0.4-0.6 g herbal substance are not plausible with  the posology of the other herbal preparations. Consequently, these preparations should not be included  in the Community monographs on hops for traditional use.   Dry extracts have only been on the market since 1993 and are consequently not considered to be  traditional.   

 ♦   References concerning the traditional medicinal use of hops as a phyto-oestrogen date back to  Koch and Heim (1953), who confirmed the folk knowledge that the menstruation cycle of female  hop pickers is influenced by picking hops. In 1961 Chury reported the oestrogenic activity for a  saponified ethanolic extract of hops, where after several hop containing cosmetic preparations  have been patented. In 1973 Fenselau and Talahay stated that brewing baths containing hop  extracts (30%) were taken in Germany for the treatment of a variety of gynaecological disorders.  In 1988 the chemical structure of the active oestrogenic principle was elucidated and in 1999 with  Milligan the modern understanding of the in vitro and in vivo oestrogenic activity of hops began.  Since then, various dried extracts prepared with ethanolic-water mixtures have been standardised  on 8-prenyl-naringenin and sometimes other prenylflavonoids. Several pharmacological,  toxicological and clinical studies with these standardised extracts have been carried out to  investigate their usefulness as drugs to alleviate menopausal discomforts.   Although these studies are of interest, the findings are not yet sufficient to support a marketing  authorisation.   Moreover, as these extracts are enriched in 8-prenylnaringenin and prepared with modern techniques  such as supercritical CO 2  extraction, they cannot be considered to be traditional.    

    Consequently, a period of at least 30 years of traditional use of hop strobiles and its preparations is  only fulfilled for their sedative effects. Since the use of dried extracts for this indication has only been  introduced since 1993, only hydroalcoholic liquid extracts including also sweet wine and dried  inflorescences as such or as infusions can be accepted as traditional herbal medicinal products. 

Pharmacodynamics    
Sedative effects      

In vitro studies    Over the past decade considerable pharmacological research has been carried out on hop strobiles and  its constituents particularly with respect to oestrogenic activity. However, the publications on in vitro  studies relating to the sedative effects of hops are very scarce.   On the contrary, some spasmolytic effects have been found for hops.   
An alcoholic extract of hop strobile (1 g of dried drug in 10 ml of 70% ethanol) produced a strong  spasmolytic effect on isolated smooth muscle from guinea pig intestine with ED 50  values equivalent to  37x10 -6  g of hop strobile per ml for acetylcholine-induced contractions compared to 60x10 -9  g/ml with  atropine, and 39x10 -6  of hop strobile per ml for bariumchloride-induced contractions compared to  57x10 -7  g/ml with papaverine. The extract also inhibited contractions of rat uterus with an ED 50   equivalent to 31x10 -6  g of hop strobile per ml (Caujolle et al., 1969).  Also an effect on the calcium flux has been detected.  A methanolic extract from hop strobile showed strong inhibitory activity on calcium fluxes, inhibiting  depolarization-induced  45 Ca 2+  uptake in clonal rat pituitary cells by 94,7% at 20 µg/ml (p<0.001).   The activity was attributed to prenylated flavonoids, although individual compounds from hop strobile  have not so far been tested in this way (Rauha et al., 1999).    
Recently, Meissner and Häberlein (2006) investigated the influence of xanthohumol (X) on the  binding of muscimol-Alexa-Fluor 532 (Mu-Alexa), a fluorescently labeled GABA A  receptor agonist  by fluorescence correlation spectroscopy. An incubation of hippocampal neurons with 75 nM of X  increased the specific Mu-Alexa binding with ca. 17%, which was selectivly found in GABA A   receptor Mu-Alexa complexes with hindered lateral motility [D bound2  = (0,11 ± 0,03) µm 2/ s ) ]    as described with midazolam, a benzodiazepine agonist. It was further shown that the modulatory  activity of X on the GABA A  receptor was not mediated via an interaction with benzodiazepine  receptors. The authors concluded that X may play an important role for the sedative effects of hop  preparations.    

In vivo studies    Old reports have indicated that preparations of hops have sedative-like activity in frogs (Staven- Groenberg, 1928 ; Munch et al., 1933 ; Steidle, 1932), pigeons (Sikorski and Rusiecki, 1938), gold  fish (Bouchardy, 1953) and golden carp (Grumback and Mirimanoff, 1955). According to Wohlfart  (1982, 1993), however, these animal tests show many methodological shortcomings.  Only a few animal experiments have been carried out to study the supposed sedating effects of hop  extracts in recent times. Following gavage of different extracts from hops or lupulone, Hänsel and  Wagener (1967) observed no indication of sedation in mice or rats. They used three hop extracts, two  produced with ethanol and another one with methylisobutylketone. Both ethanolic extracts were dried  and administered in oil. Locomotor activity was unaffected up to doses of 500 mg/kg bw and no  antagonistic effect against metamphetamine-induced stimulation was observed. Hexobarbital-induced  © 
sleeping time remained unchanged. In the Rotarod test up to 200 mg/kg bw caused no impairment of  coordination, and no muscle relaxation was observed.  

On the contrary, Bravo et al. (1974) described a reduction in locomotor behaviour of mice following  the intraperitoneal administration of three different extracts of hops (aqueous, ethereous and  alcoholic). The ethereous one was the most active, since it completely inhibited mice motor activity,  20 minutes after injection. Since, however, this effect was only seen in very high doses   (200 mg extract/20 g mouse) it cannot be responsible for the claimed sedative effect in patients. On the  other hand, this study clearly showed that the sedative effect of hops is strongly dependent on the type  of solvent used for the extraction procedure.    Lee et al. (1993a) observed a dose-dependent suppression of spontaneous locomotor activity in mice  after the intraperitoneal administration of 100 mg/kg (p<0.05), 250 mg/kg and 500 mg/kg (p<0.001) of  hop extract (96% ethanolic dry extract). 

The same authors further investigated the CNS effects of hop  extract, using other behavioural tests such as potentiation of pentobarbital-induced sleep, hypothermic  analysis and anticonvulsant tests (Lee et al., 1993b). Pentobarbital-induced sleeping time increased  dose-dependently ; not significant at 100 mg/kg, by 1,9-fold at 250 mg/kg (p<0,05) and 2,6-fold at   500 mg/kg (p<0,01). In the hot plate test, latency time for licking the forepaws increased with doses of  100 and 250 mg/kg (p<0,01). Rotarod performance decreased by 59% and 65% respectively at   250 mg/kg, and 500 mg/kg (p < 0,001 after 120 minutes). The time to onset of convulsion and survival  time after administration of pentylenetetrazole were significantly lengthened by 500 mg/kg (p<0,001),  but not by 250 mg/kg. A significant and time dependent fall in rectal temperature was observed after a  dose of 500 mg/kg (p<0,001 after 120 minutes). Thus hop strobile extract showed sedative and  hypnotic properties at lower doses (100-250 mg/kg), and at a higher dose of 500 mg/kg it also  produced anticonvulsive and hypothermic effects.  The relevance of these findings remains unclear, since all experiments were carried out after  intraperitoneal injection and no experiments were done following oral application, so that the  bioavailability of the preparation used remains questionable.    

In a recent publication (Zanoli et al., 2005), the central effects of a hop CO 2  extract and a fraction  containing the α-acids were studied in animal experiments following oral application of the hop  extract dissolved in Tween 80 (10%) or the α-acid fraction dissolved in peanut oil. Acute effects on  locomotor activity and pentobarbital sleeping time were studied, as well as behavioural parameters in  the elevated maze and the forced swimming test. The authors observed a significant increase of the  pentobarbital-induced sleeping time in rats without affecting the latency to the loss of the righting  reflex. This effect was dose-dependent starting from a minimal dose of 10 mg/kg.  Neither the extract  nor its α-acid fraction effected the locomotor activity in the open-field test or excerted an anxiolytic  effect in rats submitted to the elevated plus- maze test.  Interestingly, both hop CO 2  extract and the α-acids containing fraction significantly reduced the period  of immobility in the forced swimming test, when administered three times (24 h, 5 h and 1 h), before  the test indicating an antidepressant activity.   It was concluded that hop CO 2  extract and a hops containing α-acids fraction exert a pentobarbital- enhancing property without influencing the motor behaviour of rats and an antidepressant activity.  These results seem to show that the α-acids present in hop CO 2  extract can explain the use of hops in  sleep disturbances and that the α-acids could be a new class of compounds for the development of  natural antidepressant agents.    

More recently, Schiller et al. (2006) confirmed the sedating effects of the liphophilic extract reported  by Zanoli et al. (2005). They investigated several ethanolic extracts (40% v/v and 90% m/m) and   CO 2  extracts from diverse hop varieties as well as α-acids and β-acids fractions and pure hop oil.   All hop extracts increased ketamine-induced sleeping time in mice. The increase in duration of  ketamine narcosis proved to be a specific central effect and not caused by a pharmacokinetic  interaction, as could be confirmed by a comparable increase in ether-induced sleeping time. In contrast  to the findings of Zanoli et al. they also observed a reduction of locomotor activity. The low doses  Zanoli et al. applied (20 mg/kg/bw as maximum) may be the reason for this discrepancy.   Like Zanoli et al. no anxiolytic effects of hop preparations were found. A decrease in body  temperature induced by all hop extracts as additional parameter was observed, which confirms the  sedating activity of the hop preparations. 

The results of Schiller et al. are similar to those of Lee et al. (2003), who found a marked sedation viz. a reduction of locomotor activity, increase of pentobarbital- induced sleeping time and antagonistic effects against pentylenetetrazol-induced convulsions  following intraperitoneal injection of a hop extract. On the contrary, the results of Hänsel and  Wagener (1967) are in clear contrast to the findings of Schiller et al. (2006). The latter authors explain  this discrepancy by the use of different raw materials, different conditions of storage by which the  content of α- and β-acids might be reduced significantly and different extraction solvents used.  Finally, Schiller et al. showed that not only the α-acids, but also the β-acids and the hop oil, although  to a lesser extent, exert distinct sedating effects and contribute to the activity of the plants. They also  do not rule out the presence of further sedating components in hops.    

A degradation product of the bitter acids, humulones and lupulones, the five carbon olefinic alcohol,  2’-methyl-3-buten-2-ol, given intraperitoneally to mice at high dosage, 800 mg/kg showed central  nervous depressant activity (Hänsel et al., 1980 ; Wohlfart et al., 1983a). Although present only in  small amounts in fresh hops, higher levels of this compound may be generated in vivo by metabolism  of the bitter acids, reaching its maximum concentration after 2 years of storage at room temperature  (Hänsel et al., 1982 ; Wohlfart et al., 1982, Wohlfart, 1983b, Hänsel and Schultz, 1986)). The sedative  effect of this alcohol is comparable, in the same dosage range, to that of the structurally related drug  methylpentynol (Wohlfart et al., 1983a).  Thus, if this compound can fully explain the sedative activity attributed to hops, than it must be  formed in vivo from hop constituents such as bitter acids, that would then be considered as   “pro-drugs” analogous to the case of the oestrogenic activity (Chadwick et al., 2006).    The hypothesis, however that this alcohol can be formed in vivo by metabolisation of α-acids has not  been demonstrated to date (Zanoli et al., 2005). Similarly the proposal that the sedative effect of hops  was due to its content of myrcene, which has shown to have analgesic activity in mice (Hänsel and  Wohlfart, 1980) has not been established.  

Recently, Grundmann et al. (2006) showed that the hypothermic effects of hops could be antagonized  with the competitive melatonin receptor antagonist luzindole. Based upon a study in which it was  found that a combination of valerian and hops interacts with serotoninergic 5-HT 4e , 5-HT 6 , 5-HT 7  and  melatoninergic ML 1  and ML 2  receptors (Abourashed et al., 2004 ; Butterweck et al., 2007, Brattström,  2007), these authors evaluated the hypothermic activity of hop extract in mice. In a dosage of   250 mg/kg hops extract significantly decreased body temperature in male BL6/C57 mice (ΔT-1,1°C)   2 h after oral administration. The effects of the plant extract were comparable to melatonin (50 mg/kg,  ΔT-0,8°C, 2 h after i.p. injection). The hypothermic effects of both, melatonin and hop extract could  be antagonised with the competitive melatonin receptor antagonist luzindole.  The authors concluded that this data suggest that the hypothermic effects of hop extract are mediated  through activation of melatonin receptors. Since it is known that melatonin has both hypnotic and  hypothermic effects at physiological levels and that the hypnotic effect may be mediated via the  hypothermic action of melatonin (Zemlan et al., 2005), a similar effect may be suggested for hop  extract. The authors also concluded that neither the α- and β-acids, nor the essential oil were  responsible for these effects (Personal communication by Butterweck).

Sedative effects  
♦   Although no in vitro studies, directly related to the sedative activity of hop strobiles have been  published, nevertheless several studies in animals have been carried out to investigate the  neuropharmacological properties of Humulus lupulus, traditionally used in the treatment of  different CNS disorders such as insomnia, excitability and restlessness.   
One of the studies showed that hop strobile extracts exert sedative and hypnotic properties in mice  at lower doses (100-250 mg/kg) and produce other activities such as anticonvulsive and  hypothermic effects at higher doses of 500 mg/kg.  
Hop extracts were able to prolong the pentobarbital sleeping time without affecting the latency to  the loss of the righting reflex in rats, confirming the first study concerning the hypnotic properties  and the traditional observation of sleepiness in hops-pickers. In the same study it was shown that  the α-acids were responsible for the pentobarbital sleep-enhancing properties as well as for the  antidepressant activity found for the hop strobile extract.     

In a recent study, carried out with several ethanolic and CO 2  extracts of hops, administered by  gavage to mice, it was clearly shown that all extracts reduced the spontaneous locomotor activity,  increased the ketamine-induced sleeping time and reduced body temperature, confirming a central  sedating effect. No indications of anxiolytic activity were found for any of the test preparations.  
The sedating activity could be attributed to three categories of constituents of lipophilic hop  extracts. Though the α-bitter acids proved to be the most active constituents, the β-acids and the  hop oil clearly contributed to the sedating effect of lipophilic hop extracts as well.  The authors also suggested that the contradictory results obtained by different research teams in  the determination of different pharmacological effects was due to the use of different raw  materials, different storage conditions leading to various amounts of active components and the  use of different extraction solvents for the production of the preparations.  Furthermore, candidate molecules for the sedative effects of hop strobiles such as myrcene and   2’-methyl-3-buten-2-ol have been suggested, but their role as sedative agents has not been  substantiated.    

Recently, however, it has been shown that one of the chalcones viz. xanthohumol influences the  GABA A  receptors and their lateral mobility at hippocampal neurons in a similar way as the  benzodiazepine agonist midazolam without interfering with the benzodiazepine receptors.   Thus, xanthohumol may play an important role for the sedative effect of hop preparations, but this  should be confirmed by in vivo studies.  More recently the in vitro study in which it was suggested that a combination of hops and valerian  interacts with melatoninergic ML 1  receptors, was confirmed by an in vivo investigation on mice.   
It was shown that hop extracts (250 mg/kg) had comparable hypothermic effects as melatonin   (50 mg/kg), which could be blocked by the competitive melatonin receptor antagonist luzindole.  Since it is known that the hypnotic effect of melatonin may be mediated via its hypothermic  action, a similar effect for hops may be suggested.   The authors also concluded that this effect was not due to the acids or the essential oil of hops,  since both were absent in the hop extract used in this study.

Oestrogenic effects   

In vitro studies    
Oestrogenic activity of hop strobiles    
Circumstantial evidence over many years, including menstrual disturbances reported to be common  among female hop pickers, linked hop strobiles with potential oestrogenic activity (Verzele, 1986 ;   De Keukeleire et al., 1999). In Germany, hop baths were used to treat gynaecologic disorders and hop  extracts have been reported to reduce hot flushes in menopausal women (Goetz, 1990). However,  early studies to confirm this activity experimentally were unconclusive or contradictory due to  methodology of inadequate sensitivity (De Keukeleire et al., 1997, 1999).    

In a recent screening of plant drugs for oestrogenic activity, a 50%-ethanolic extract (2 g of hop  strobile to 10 ml) exhibited binding to oestrogen receptors in intact, oestrogen-dependent [ER(+)], human breast cancer MCF-7 cells with a potency equivalent to 0,5 µg of oestradiol per 2 g of dried  strobile (for comparison, the potencies of 2 g of thyme or red clover were equivalent to 0,5 or 3 µg of  oestradiol, respectively).  The extract also showed significant ability to stimulate cell proliferation in ER(+)T47D, but not in  ER(-)MDA 468, breast cancer cells (Zava et al., 1998). In contrast, in a different series of experiments,  a similarly-prepared extract of hop strobile at concentrations of 0,01-1,0% V/V was found to  significantly inhibit serum-stimulated growth of ER(+)T47D breast cancer cells (p<0,001)   (Dixon-Shanies and Shaikh, 1999).    

Ovarian cells isolated from immature female rats, which 48 hours previously had been injected  (primed) with pregnant mare’s serum gonadotrophin, were incubated with follicle-stimulating  hormone to induce oestradiol secretion. Addition to the culture medium of purified water-soluble  fractions F 1  or F 2  from defatted hop strobile extract reduced the amounts of oestrogen E 2  released from  the ovarian cells (p<0,01) with a probably related decrease in cAMP release (p<0,05)   (Okamato and Kumai, 1992).    

In 2005 Overk et al. compared the oestrogenicities of the extracts of hops and red clover (Trifolium  pratense) and those of their individual constituents, including respectively prenylated flavanones and  isoflavonoids, using a variety of in vitro oestrogenic assays. The hop extract consisted of a chloroform  partition of a methanolic extract from a previously SF-C0 2 -extracted Nugget hops cultivar and the red  clover extract was an ethanolic extract containing 30% isoflavonoids prepared for a phase II clinical  trial.  The IC 50  values for the oestrogen receptor α and β binding assays (according to Obourn et al. (1993)  and Liu et al. (2001)), were 15 and 27 µg/ml, respectively for hops and 18,0 and 2,0 µg/ml,  respectively for the red clover extract.  Both of the extracts demonstrated also significant activities of transiently transfected ERE-luciferase,  quantitative RT-PCR of an oestrogen-inducible gene, and AP-enzyme induction assays (EC 50  values of  1,1 for hop extracts and 1,9 µg/ml for red clover extracts). 


In vivo studies    
Antigonadotrophic effects of hop strobiles    
Purified water-soluble fractions from defatted hop strobile extract were administered subcutaneously  twice daily for 3 days to immature female rats primed with 25 IU of pregnant mare’s serum  gonadotrophin (PMSG). None of the fractions induced a change in uterine weights. However, fractions  F 1  (20 mg/rat) and F 2  (50 mg/rat) significantly suppressed PMSG-induced gain in ovarian weights by  about 25% (p<0,05) compared to controls. Under the same conditions, two further fractions (4 mg/rat)  purified from F 1  suppressed gain in ovarian weights by 42% and 33% (p<0,01) compared to controls  (Kumai and Okamoto (1984). In further experiments on PMSG-primed immature rats, by comparison  with saline-treated control animals, subcutaneously administered fractions F 1  and F 2  reduced the  number of ovulations (p<0,05) ; suppressed levels of serum luteinizing hormone (p<0,001) ;  suppressed thymidine kinase activity in uterine tissue (p<0,01) ; reduced 17β-oestradiol E 2  secretion in  cultures of ovarian cells from the rats (p<0,001) ; and reduced progesterone production in cultures of  luteal cells from the rats (p<0,05 to p<0,001) (Okamato and Kumai,  1992). 

Oestrogenic effects  
♦   In contrast to the studies on the sedative effects, the phyto-oestrogen, responsible for the  oestrogenic activity of hop strobiles has been isolated and identified as the prenylated flavanone,  8-prenylnaringenin or hopein (8-PN). The oestrogenic activity proved to be considerably greater  than that of established phyto-oestrogens such as coumestrol (present in red clover) and genistein  and daidzein (present in soy). 

The oestrogenicity has been examined in great detail by a number of independent research groups worldwide. The other prenylated flavonoids were extremely  weakly oestrogenic or devoid of any oestrogenicity. 8-PN exerts its activity through oestrogen  receptor-mediated mechanisms. It binds very strongly to both oestrogen receptor isoforms   (ER α  and ER β ), but in contrast to most known phyto-oestrogens, 8-PN is selective for the  oestrogen receptor-α. As such it mimics the effects of the endogenous 17β-oestradiol. Both have  similar profiles, however, the activity of 8-PN is 5- to 100-fold weaker depending on the test  system and the particular reaction conditions.  8-PN is orally active in ovariectomized mice as a significant increase in vascular permeability was  observed within 4 hours after subcutaneous injection of both 17β-oestradiol and a 100-fold dose of  8-PN. Administration of 17β-oestradiol (100 ng/ml) or 8-PN (100 µg/ml) to the drinking water  showed, after 71 h, a considerable increase in vaginal mitosis. Although 17β-oestradiol caused  also a substantial increase in uterus weight and in epithelial mitosis, significant differences with   8-PN were not observed.     

In other experiments, ovariectomized rats were injected with 8-PN over a period of 14 days.   A favourable effect on bone metabolism was observed. Removal of the ovaria normally results in a  drastic increase in levels of bone resorption markers in urine, a decrease in mineral bone density  and a reduction in uterus weight. Treatment with 17β-oestradiol (0,01 mg/kg/day) or 8-PN   (30 mg/kg/day) gave quantitatively comparable effects on bone and uterus showing that 8-PN  functions as an oestrogenic agonist.    
The influence of 8-PN on oestrogen-related gen expression in liver and uterus tissues was  investigated in rats. At a 100-fold dose with respect to 17β-oestradiol, 8-PN induced a  qualitatively similar, but less pronounced expression profile. On the other hand a stronger  upregulation of the expression of IGFBP-1 was observed. This growth factor has been correlated  to an improvement of the vascular endothelial function and blood pressure homeostasis, while  higher concentrations of IGFBP-1 are also associated with a decreased risk of prostate cancer.    

In conclusion, 8-PN, present in hop strobiles at levels of 25-60 mg/kg, should be considered to be the active oestrogenic compound of hops. It should be noticed that desmethyl-xanthohumol serves as   pro-oestrogen, since it can be metabolised into a mixture of 8-PN and 6-PN. 

Hop essential oil and hop acids 

 ♦ Antimicrobial activity 
 Some antimicrobial activity of hop essential oil has been reported (Racz et al., 1980 ; Grange and Davey, 1990 ; Langezaal et al., 1992 ; Simpson and Smith, 1992 ; Ohsugi et al., 1997 ; Tagashira et al., 1997 ; Matos et al., 2001) and hops are included in various cosmetic preparations. The lupulones (β-acids) have a longstanding reputation as antibacterials (against gram-positive bacteria), which had led to some applications of hop products rich in β-acids, particularly in the sugar industry. It appears that the three prenyl groups present in lupulone interfere with the building up and the functioning of the bacterial cell walls leading eventually to leakage of the cell contents. Resistance of gram-negative bacteria to the resin acids is attributed to the presence of a phospholipid- containing outer membrane, as lupulones and humulones are inactivated by serum phospholipids (Teuber and Schmalreck 1973). Structure-activity relationship studies have indicated the requirement of a hydrophobic molecule and a six-membered central ring for such activity (Schmalreck et al., 1975). The acids are thought to possess little activity towards fungi or yeasts. However, antifungal activity has been documented for the bitter acids towards Trichophyton, Candida, Fusarium and Mucor species (Mizobuchi and Sato, 1984). 

♦ Antidiabetic activity 
Isohumulones are the main bittering principles in beer. Recently, interesting antidiabetic properties of isohumulones have become apparent (Kondo, 2003). Via a reporter system, it was found that agonistic effects were exerted on the activity of the nuclear receptors PPARalpha (‘Peroxisome Proliferator- Activated Receptor-alpha’) and PPARgamma. The PPAR’s are important regulators of the glucose and fat metabolisms and agonists are applied to treat non-insulin-dependent diabetes (diabetes type II) and hyperlipidemia. Administration of isohumulones to a mouse model for diabetes type II (KK-A y ) led to a decrease of plasma triglycerides and free fatty acids in a dose-dependent manner. Moreover, the glucose levels were significantly diminished in KK-A y -mice. The results indicate that intake of isohumulones may favourably influence conditions of hyperglycemia and hypertriglyceridemia. Treatment of 20 subjects suffering from mild diabetes with isohumulones (twice a day during 12 weeks), in dosages that were equivalent to only a few glasses of strongly hopped beers, showed a decline in glucose levels and other parameters, indicating that oral intake of isohumulones ameliorates insulin sensitivity In patients with diabetes type II. 

 ♦ Activity on osteoporosis 
 Humulone, the major constituent of the mixture of α-acids, has been shown to inhibit bone resorption using an in vitro “pit formation assay” (formation of pits on dentine slices incubated with mouse bone cells). Xanthohumol and humulone have been identified as inhibitors of bone resorption at concentrations at or above 10 -6 and 10 -11 , respectively (p<0,01). Humulone showed high inhibitory activity with an IC 50 of 5,9x10 -9 M (Tobe et al., 1997a). These findings indicate that hops may be active against osteoporosis. It should be noted, however, that xanthohumol and especially humulone, have no oestrogenic activities, which may indicate that the inhibition of bone resorption of hops is not associated with oestrogenicity (De Keukeleire et al., 1999). 

 ♦ Antinflammatory activity 
 Humulone also proved to be a potent inhibitor of the expression of cyclooxygenase-2 (COX-2) via interaction with NFκB, which translates into pronounced anti-iflammatory activity (Yamamoto et al., 2000). Also in vivo anti-inflammatory effects have been seen for humulone, which seemed to be the active anti-inflammatory agent of hop strobiles. A dry methanolic extract of hop strobile, applied topically at 2 mg/ear, inhibited 12-0-tetradecanoylphorbol-13-acetate (TPA)-induced ear oedema in mice by 90% (p<0,01) six hours after TPA treatment. Humulone, isolated from hop strobile by bioassay-guided fractionation and identified as an anti-inflammatory constituent, inhibited the oedema with a ID 50 of 0,2 mg/ear (ID = inhibitory dose). Topically-applied humulone also inhibited arachidonic acid-induced inflammatory ear oedema in mice with an ID 50 of 2,2 mg/ear (p<0,01 against controls) compared to 0,4 mg/ear (p<0,01) for indometacin (Yasukawa et al., 1993). 

 ♦ Antiproliferative activity 
 Humulone has been found to inhibit angiogenesis (formation of new blood vessels, which is essential for tumour growth), as well as proliferation (uncontrolled growth) of endothelial cells (Shimamura et al., 2001). The latter effect has been confirmed by an in vivo test, in which tumour promotion could be inhibited. Humulone applied topically at 1 mg/mouse to the backs of mice markedly inhibited the tumour- promoting effect of TPA on 7,12-dimethylbenz[a]-anthracene-initiated skin tumour formation. In the control group 100% of mice developed tumours (first tumour appeared in week 6), compared to only 7% in the humulone-treated group (first appearance in week 16). Humulone treatment resulted in a 99% reduction in the average number of tumours per mouse at week 18 (p<0,01) (Yasukawa et al., 1995).
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