Elsevier

Maturitas

Volume 54, Issue 2, 20 May 2006, Pages 164-175
Maturitas

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

https://doi.org/10.1016/j.maturitas.2005.10.005Get rights and content

Abstract

Objectives

To examine the efficacy of a hop extract enriched in 8-prenylnaringenin (8-PN, the phytoestrogen in hops, Humulus lupulus L.) on relief of menopausal discomforts.

Methods

A prospective, randomized, double-blind, placebo-controlled study over 12 weeks with 67 menopausal women, who were administered a hop extract standardized on 8-PN (100 or 250 μg). The responses were determined by means of a modified Kupperman index (KI) and a patients’ questionnaire.

Results

All groups, including placebo, showed a significant reduction of the KI both after 6 weeks and after 12 weeks. The hop extract at 100 μg 8-PN was significantly superior to placebo after 6 weeks (P = 0.023) but not after 12 weeks (P = 0.086). No dose–response relationship could be established, as the higher dose (250 μg) was less active than the lower dose both after 6 weeks and after 12 weeks. Still, a trend for a more rapid decrease of KI was noticed for both active groups as compared to placebo. In particular, the decrease in hot flush score (isolated from the KI) was found significant for both treatment groups after 6 weeks (P < 0.01) with respect to placebo. Results of the patients’ questionnaire were consistent with those of the KI, with the most pronounced effects being observed for the 100-μg treatment.

Conclusions

Daily intake of a hop extract, standardized on 8-PN as a potent phytoestrogen, exerted favorable effects on vasomotor symptoms and other menopausal discomforts. Hop-derived prenylated flavonoids may provide an attractive addition to the alternative treatments available for relief of hot flushes and other menopausal discomforts.

Introduction

It is generally acknowledged that postmenopausal hormone therapy (HT) is the most efficient treatment for the relief of climacteric discomforts and symptoms [1]. Large trials have proven that HT prevents osteoporosis, while at dosages used in most trials, HT is associated with an increase in thrombosis and breast cancer [2], [3], [4]. Even after more than 50 years of experience with HT, many questions remain unresolved. There is still much debate on whether HT is cardioprotective or not. The International Menopause Society (IMS) has recently published a number of guidelines [5]. It is obvious that the dosage of the estrogenic component of HT is critical in its causal relation with the increase in thrombotic events. These events may have obscured a possible cardiovascular protective influence. Recent randomized trials indicated that, even in severely cardiovascular compromised patients, normal-dose HT was not associated with an increased rate of thrombosis [6], [7]. Even with a further reduction of estrogen, HT remains efficient for the prevention of bone loss [8]. HT, containing a very low dose of estrogen or weaker, naturally available estrogens, could also be of health benefit, without increasing the risk of thrombosis and breast cancer. The North American Menopause Society (NAMS) suggests that changes in lifestyle, either alone or combined with the use of naturally available phytoestrogens, should be considered for the relief of mild vasomotor symptoms [9].

Phytoestrogens are a diverse group of polyphenolic, non-steroidal plant compounds that bind to human estrogen receptors (ERs) and cause effects comparable, although less intense, to those of endogenous steroidal estrogens [10]. Some 20 dietary supplements based on plant extracts with an association to menopausal complaints are commercially available in Belgium, the most important ones being derived from soy (Glycine max L.), red clover (Trifolium pratense L.), black cohosh (Cimicifuga racemosa L.), chaste berry (Vitex agnus-castus L.), and wild yam (Dioscorea villosa L.). Recently, a product based on hops (Humulus lupulus L.) has been introduced. Although most commercially available hop-derived preparations (often in combination with other plants, such as Valeriana officinalis L. and Melissa officinalis L.) are focused on the tranquilizing (sedative) effect of the plant, hops have been known to be estrogenic both from traditional medicine and from anecdotal reports.1 Hops are a rich source of prenylated flavonoids including 8-prenylnaringenin (8-PN), a prenylated flavanone (see Appendix A). Comparison with well-known phytoestrogens, e.g., coumestrol (from clover and/or alfalfa), and genistein and daidzein (from soy), learnt that 8-PN is currently one of the most potent phytoestrogens [11], [12], [13]. This finding has been confirmed by a number of independent research groups both by in vivo and in vitro studies [14], [15], [16], [17], [18], [19].

Surprisingly, and unlike other phytoestrogens, 8-PN was found a much weaker agonist of the estrogen receptor β (ERβ) than of the estrogen receptor α (ERα) [20], thereby closely resembling the activity profile of the endogenous 17β-estradiol (E2) [21]. Depending on the specific bioassay and the test conditions, the estrogenic potency is between 10-fold to several 100-fold less pronounced than that of E2 for both ERα and ERβ. It should be noted that 8-PN and E2 show structural similarities (see Appendix A), while the presence of a prenyl side chain at the C-8 position in 8-PN apparently results in an enhanced affinity towards the estrogen receptor, most likely as the result of a site-specific hydrophobic interaction (6-prenylnaringenin, a positional isomer of 8-PN, is at least 100-fold less active, see [11]).

8-PN exhibits estrogenic effects on bone metabolism [22]. Other biological activities of 8-PN include inhibition of angiogenesis [23] and stimulation of cell–cell adhesion [24]. Furthermore, 8-PN has been shown to significantly reduce the acetanilide 4-hydroxylase activity of CYP1A2 and the CYP1A2-mediated metabolic activation of aflatoxins B1 and M1 [25].

Until now, only one human study has been published indicating that hot flushes could be controlled by an orally administered hop extract [26]. Unfortunately, the extract used was a non-standardized aqueous extract (8-PN had not been discovered yet), while the study population was not well defined. Although a positive effect on menopausal complaints (hot flushes) was reported, it could not be attributed to either an effect via the central nervous system or via estrogenically active compounds.

The current study aimed to examine whether dietary intake of hop-derived prenylated flavonoids, as a daily administered dietary supplement standardized on 8-PN, could have beneficial effects on menopausal discomforts in post-menopausal women. Thus, a randomized, double-blind, placebo-controlled study was designed. Three groups were formed, a control group receiving a placebo and two active groups who were administered daily doses of a hop extract corresponding to a daily intake of 100 and 250 μg of 8-PN, respectively. Criteria for evaluation were a modified Kupperman index and a quality-of-life questionnaire. The modified Kupperman index served as a scoring tool by the medical professional for measuring clinical effects of treatment of menopausal discomforts [27]. A simplified patients’ questionnaire (derived from the ‘menopause-specific quality-of-life’ (MENQOL) questionnaire) was used as a self-evaluating instrument to measure the menopause-related quality of life in relation to discomforts reported by the subjects [28].

We wish to report the results of this first clinical study using a standardized hop extract.

Section snippets

Participants

Healthy women aged between 45 and 60 years, who had an intact uterus and had not experienced menses for at least 12 months, were considered for inclusion in the study. Having had mild to severe menopausal discomforts, more specifically due to hot flushes (at least 2–5 hot flushes per day corresponding to a score of at least 2 for the item ‘hot flushes’ on the modified Kupperman index) during several weeks, was a decisive criterion, while abstention of HT during at least 3 months and preferably

Results

Out of 84 women that were initially assessed for eligibility, 17 participants did not meet the inclusion criteria, as they showed less than two hot flushes per day at baseline (i.e., a score of 0 or 1 on the item ‘hot flushes’ in the Kupperman index at baseline). The other 67 participants were randomly allocated to either the placebo group (n = 26), the group taking 100 μg 8-PN (n = 20) or the group taking 250 μg 8-PN (n = 21). The participant's flow diagram is given in Fig. 1.

The drop-out rate varied

Discussion

This randomized, double-blind, placebo-controlled study demonstrated that treatment with a hop extract standardized on 8-PN (100 and 250 μg daily doses for groups 1 (G1) and 2 (G2), respectively) proved beneficial with respect to the improvement of several menopausal discomforts. A substantial decrease of the Kupperman index (KI) as assessed by the medical professional and a definite improvement in the quality-of-life as measured by a patients’ questionnaire was observed for all groups including

Conclusions

The results obtained in this prospective, randomized, double-blind, placebo-controlled study proved that administration of a hop extract standardized on 8-prenylnaringenin (daily dose of 100 μg) to post-menopausal women during 6 weeks and 12 weeks reduced discomforts and complaints associated to the menopause as expressed by the Kupperman index and by a patients’ questionnaire. In particular, rapid improvement of the incidence of hot flushes was evident. However, no dose–response relationship

Conflict of interest

The study was designed and financed by Biodynamics, Ostend, Belgium, with the principal aim of evaluating their food supplement MenoHop®. The study, the analysis, and the writing of this article, however, were done independently of Biodynamics, apart from occasional advice on matters of protocol from the Research Director of Biodynamics (SV as co-author). The supporting source had no influence on the decision to submit the results of the study for publication.

Acknowledgements

Financial support by the IWT-Vlaanderen (Institute for the Promotion of Innovation by Science and Technology in Flanders), Brussels, Belgium, is gratefully acknowledged (IWT projects 000285 and 030015). The physicians, gynaecologists, and participating women are thanked for their kind co-operation. The logistic support of Biodynamics, Ostend, Belgium, is greatly appreciated.

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