Download PDF
Planta Med 2013; 79(07): 576-579
DOI: 10.1055/s-0032-1328330
Women's Health
Mini Reviews
Georg Thieme Verlag KG Stuttgart · New York

Hop Extracts and Hop Substances in Treatment of Menopausal Complaints

Annekathrin M. Keiler
1   Institute of Zoology, Molecular Cell Physiology and Endocrinology, Technische Universität Dresden, Dresden, Germany
,
Oliver Zierau
1   Institute of Zoology, Molecular Cell Physiology and Endocrinology, Technische Universität Dresden, Dresden, Germany
,
Georg Kretzschmar
1   Institute of Zoology, Molecular Cell Physiology and Endocrinology, Technische Universität Dresden, Dresden, Germany
› Author Affiliations
Further Information

Publication History

received 20 December 2012
revised 12 February 2013

accepted 16 February 2013

Publication Date:
19 March 2013 (online)

   Permissions and Reprints

Abstract

Hop extract is a long used medicinal product and, regarding hormonal activities, in 1999 a number of prenylflavanones have been identified as its major constituents with 8-prenylnaringenin (8-PN) being the main active estrogenic compound. There have been several in vivo studies performed that demonstrate the potential of hop extract and the single compound 8-PN to alleviate climacteric symptoms like osteoporosis, vasomotoric complaints, and sexual motivation. On the other hand, only a few clinical studies have been performed so far, and these mainly focused on menopausal discomforts, especially hot flushes, yielding rather inconclusive results. Despite preferentially activating estrogen receptor α, 8-PN is only slightly uterotrophic, but it also elucidates estrogenic effects on the mammary gland. In conclusion, although hop extract and especially 8-PN are promising candidates as a relief for climacteric symptoms, data on the safety and efficacy is still scarce.

Key words

Humulus lupulus L. - Cannabaceae - menopause - 8-prenylnaringenin - xanthohumol - isoxanthohumol - safety
 

  • References

  • 1 Milligan SR, Kalita JC, Heyerick A, Rong H, Cooman LD, Keukeleire DD. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. J Clin Endocrinol Metab 1999; 84: 2249-2249
    CrossrefPubMedGoogle Scholar
  • 2 Vlietinck AJ. Assessment report for herbal substance(s), herbal preparation(s) or combinations thereof with traditional use – Humulus lupulus L., flos. London: EMEA; 2008
    CrossrefGoogle Scholar
  • 3 Milligan SR, Kalita JC, Pocock V, Kauter VVD, Stevens JF, Deinzer ML, Rong H, Keukeleire DD. The endocrine activities of 8-prenylnaringenin and related hop (Humulus lupulus L.) flavonoids. J Clin Endocrinol Metab 2000; 85: 4912-4915
    CrossrefPubMedGoogle Scholar
  • 4 Milligan S, Kalita J, Pocock V, Heyerick A, Cooman LD, Rong H, Keukeleire DD. Oestrogenic activity of the hop phyto-oestrogen, 8-prenylnaringenin. Reproduction 2002; 123: 235-242
    CrossrefPubMedGoogle Scholar
  • 5 Zierau O, Gester S, Schwab P, Metz P, Kolba S, Wulf M, Vollmer G. Estrogenic activity of the phytoestrogens naringenin, 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin. Planta Med 2002; 68: 449-451
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Schaefer O, Hümpel M, Fritzemeier KH, Bohlmann R, Schleuning WD. 8-Prenyl naringenin is a potent ERα selective phytoestrogen present in hops and beer. J Steroid Biochem Mol Biol 2003; 84: 359-360
    CrossrefPubMedGoogle Scholar
  • 7 Diel P, Thomae RB, Caldarelli A, Zierau O, Kolba S, Schmidt S, Schwab P, Metz P, Vollmer G. Regulation of gene expression by 8-prenylnaringenin in uterus and liver of Wistar rats. Planta Med 2004; 70: 39-44
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Zierau O, Kretzschmar G, Möller F, Weigt C, Vollmer G. Time dependency of uterine effects of naringenin type phytoestrogens in vivo . Mol Cell Endocrinol 2008; 294: 92-99
    CrossrefPubMedGoogle Scholar
  • 9 Kitaoka M, Kadokawa H, Sugano M, Ichikawa K, Taki M, Takaishi S, Iijima Y, Tsutsumi S, Boriboon M, Akiyama T. Prenylflavonoids: a new class of non-steroidal phytoestrogen (Part 1). Isolation of 8-isopentenylnaringenin and an initial study on its structure-activity relationship. Planta Med 2007; 64: 511-515
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Komatsu M, Yokoe I, Shirataki Y. Studies on the constituents of Sophora species. XIII. Constituents of the aerial parts of Sophora tomentosa L. Chem Pharm Bull (Tokyo) 1978; 26: 3863-3870
    CrossrefPubMedGoogle Scholar
  • 11 Bohlmann F, Zdero C, King RM, Robinson H. New prenylflavanoids from Marshallia grandiflora . Phytochemistry 1979; 18: 1246-1247
    CrossrefPubMedGoogle Scholar
  • 12 Chadwick LR, Nikolic D, Burdette JE, Overk CR, Bolton JL, van Breemen RB, Fröhlich R, Fong HHS, Farnsworth NR, Pauli GF. Estrogens and congeners from spent hops (Humulus lupulus). J Nat Prod 2004; 67: 2024-2032
    CrossrefPubMedGoogle Scholar
  • 13 Chadwick LR, Pauli GF, Farnsworth NR. The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties. Phytomedicine 2006; 13: 119-131
    CrossrefPubMedGoogle Scholar
  • 14 Stevens JF, Miranda CL, Buhler DR, Deinzer ML. Chemistry and biology of hop flavonoids. JASBC 1998; 56: 136-145
    PubMedGoogle Scholar
  • 15 Stevens JF, Taylor AW, Deinzer ML. Quantitative analysis of xanthohumol and related prenylflavonoids in hops and beer by liquid chromatography–tandem mass spectrometry. J Chromatogr A 1999; 832: 97-107
    CrossrefPubMedGoogle Scholar
  • 16 Possemiers S, Heyerick A, Robbens V, De Keukeleire D, Verstraete W. Activation of proestrogens from hops (Humulus lupulus L.) by intestinal microbiota; conversion of isoxanthohumol into 8-prenylnaringenin. J Agric Food Chem 2005; 53: 6281-6288
    CrossrefPubMedGoogle Scholar
  • 17 Possemiers S, Bolca S, Grootaert C, Heyerick A, Decroos K, Dhooge W, Keukeleire DD, Rabot S, Verstraete W, Wiele de TV. 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 2006; 136: 1862-1867
    PubMedGoogle Scholar
  • 18 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 2006; 34: 1152-1159
    CrossrefPubMedGoogle Scholar
  • 19 Bolca S, Possemiers S, Maervoet V, Huybrechts I, Heyerick A, Vervarcke S, Depypere H, De Keukeleire D, Bracke M, De Henauw S, Verstraete W, Van de Wiele T. Microbial and dietary factors associated with the 8-prenylnaringenin producer phenotype: a dietary intervention trial with fifty healthy post-menopausal Caucasian women. Br J Nutr 2007; 98: 950-959
    PubMedGoogle Scholar
  • 20 Holick MF, Lamb JJ, Lerman RH, Konda VR, Darland G, Minich DM, Desai A, Chen TC, Austin M, Kornberg J, Chang JL, Hsi A, Bland JS, Tripp ML. 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; 28: 342-350
    CrossrefPubMedGoogle Scholar
  • 21 Lamb JJ, Holick MF, Lerman RH, Konda VR, Minich DM, Desai A, Chen TC, Austin M, Kornberg J, Chang JL, Hsi A, Bland JS, Tripp ML. Nutritional supplementation of hop rho iso-alpha acids, berberine, vitamin D3, and vitamin K1 produces a favorable bone biomarker profile supporting healthy bone metabolism in postmenopausal women with metabolic syndrome. Nutr Res 2011; 31: 347-355
    CrossrefPubMedGoogle Scholar
  • 22 Ming LG, Ge BF, Wang MG, Chen KM. Comparison between 8-prenylnarigenin and narigenin concerning their activities on promotion of rat bone marrow stromal cellsʼ osteogenic differentiation in vitro . Cell Prolif 2012; 45: 508-515
    CrossrefPubMedGoogle Scholar
  • 23 Hümpel M, Isaksson P, Schaefer O, Kaufmann U, Ciana P, Maggi A, Schleuning W-D. Tissue specificity of 8-prenylnaringenin: protection from ovariectomy induced bone loss with minimal trophic effects on the uterus. J Steroid Biochem Mol Biol 2005; 97: 299-305
    CrossrefPubMedGoogle Scholar
  • 24 Sehmisch S, Hammer F, Christoffel J, Seidlova-Wuttke D, Tezval M, Wuttke W, Stuermer K, Stuermer E. Comparison of the phytohormones genistein, resveratrol and 8-prenylnaringenin as agents for preventing osteoporosis. Planta Med 2008; 74: 794-801
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Freedman RR. Hot flashes: behavioral treatments, mechanisms, and relation to sleep. Am J Med 2005; 118: 124-130
    CrossrefPubMedGoogle Scholar
  • 26 Berendsen HH, Weekers AH, Kloosterboer HJ. Effect of tibolone and raloxifene on the tail temperature of oestrogen-deficient rats. Eur J Pharmacol 2001; 419: 47-54
    CrossrefPubMedGoogle Scholar
  • 27 Bowe J, Li XF, Kinsey-Jones J, Heyerick A, Brain S, Milligan S, OʼByrne K. The hop phytoestrogen, 8-prenylnaringenin, reverses the ovariectomy-induced rise in skin temperature in an animal model of menopausal hot flushes. J Endocrinol 2006; 191: 399-405
    CrossrefPubMedGoogle Scholar
  • 28 Dennerstein L, Alexander JL. The menopause and sexual functioning. Annu Rev Sex Res 2003; 14: 64-82
    PubMedGoogle Scholar
  • 29 Ågmo A, Turi AL, Ellingsen E, Kaspersen H. Preclinical models of sexual desire: conceptual and behavioral analyses. Pharmacol Biochem Behav 2004; 78: 379-404
    CrossrefPubMedGoogle Scholar
  • 30 Di Viesti V, Carnevale G, Zavatti M, Benelli A, Zanoli P. Increased sexual motivation in female rats treated with Humulus lupulus L. extract. J Ethnopharmacol 2011; 134: 514-517
    CrossrefPubMedGoogle Scholar
  • 31 Rad M, Hümpel M, Schaefer O, Schoemaker RC, Schleuning WD, Cohen AF, Burggraaf J. Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women. Br J Clin Pharmacol 2006; 62: 288-296
    CrossrefPubMedGoogle Scholar
  • 32 Heyerick A, Vervarcke S, Depypere H, Bracke M, Keukeleire DD. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas 2006; 54: 164-175
    CrossrefPubMedGoogle Scholar
  • 33 Erkkola R, Vervarcke S, Vansteelandt S, Rompotti P, De Keukeleire D, Heyerick A. A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts. Phytomedicine 2010; 17: 389-396
    CrossrefPubMedGoogle Scholar
  • 34 Morali G, Polatti F, Metelitsa E, Mascarucci P, Magnani P, Brunenghi Marrè G. Open, non-controlled clinical studies to assess the efficacy and safety of a medical device in form of gel topically and intravaginally used in postmenopausal women with genital atrophy. Arzneimittelforschung 2011; 56: 230-238
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Alder E. The Blatt-Kupperman menopausal index: a critique. Maturitas 1998; 29: 19-24
    CrossrefPubMedGoogle Scholar
  • 36 Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SAA, Howard BV, Johnson KC, Kotchen JM, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Womenʼs Health Initiative randomized controlled trial. JAMA 2002; 288: 321-333
    CrossrefPubMedGoogle Scholar
  • 37 Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. The Lancet 2002; 360: 942-944
    CrossrefPubMedGoogle Scholar
  • 38 Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. The Lancet 2003; 362: 419-427
    CrossrefPubMedGoogle Scholar
  • 39 Beral V. Ovarian cancer and hormone replacement therapy in the Million Women Study. The Lancet 2007; 369: 1703-1710
    CrossrefPubMedGoogle Scholar
  • 40 Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Womenʼs Health Initiative Randomized Trial. JAMA 2003; 289: 3243-3253
    CrossrefPubMedGoogle Scholar
  • 41 Chlebowski RT, Kuller LH, Prentice RL, Stefanick ML, Manson JE, Gass M, Aragaki AK, Ockene JK, Lane DS, Sarto GE, Rajkovic A, Schenken R, Hendrix SL, Ravdin PM, Rohan TE, Yasmeen S, Anderson G. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med 2009; 360: 573-587
    CrossrefPubMedGoogle Scholar
  • 42 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. Comparison of the in vitro estrogenic activities of compounds from hops (Humulus lupulus) and red clover (Trifolium pratense). J Agric Food Chem 2005; 53: 6246-6253
    CrossrefPubMedGoogle Scholar
  • 43 Rimoldi G, Christoffel J, Wuttke W. Morphologic changes induced by oral long-term treatment with 8-prenylnaringenin in the uterus, vagina, and mammary gland of castrated rats. Menopause 2006; 13: 669-677
    CrossrefPubMedGoogle Scholar
  • 44 Wang YJ, Dou J, Cross KP, Valerio Jr. LG. Computational analysis for hepatic safety signals of constituents present in botanical extracts widely used by women in the United States for treatment of menopausal symptoms. Regul Toxicol Pharmacol 2011; 59: 111-124
    CrossrefPubMedGoogle Scholar
  • 45 Kretzschmar G, Zierau O, Wober J, Tischer S, Metz P, Vollmer G. Prenylation has a compound specific effect on the estrogenicity of naringenin and genistein. J Steroid Biochem Mol Biol 2010; 118: 1-6
    CrossrefPubMedGoogle Scholar