twitter

Tuesday 25 April 2017

Herbal preparations for the menopause: beyond isoflavones and black cohosh

Maturitas
Volume 77, Issue 2, February 2014, Pages 191–194
Review

Herbal preparations for the menopause: Beyond isoflavones and black cohosh


http://doi.org/10.1016/j.maturitas.2013.11.001
Get rights and content

Abstract

Complementary and alternative medicines (CAM) such as isoflavones and black cohosh are commonly used to deal with menopausal symptoms, but benefit a limited proportion of women. The aim of this minireview is to summarize the evidence of the efficacy and safety of other herbal preparations. Randomized controlled trials (RCTs) find that the extracts of Mediterranean pine bark (Pycnogenol®), linseed, and Lepididium meyenii (Maca) reduce vasomotor symptoms. The results of RCTs of the hop flavonoid 8-prenylnaringenin are conflicting. Animal and human studies suggest that Dioscorea villosa (Wild yam),and Broccoli may protect against osteoporosis and breast and gynecological cancers but further evidence is required. Linseed may protect against breast cancer but the results are conflicting.

Keywords

  • Menopause;
  • Treatment;
  • Herbal medicine;
  • Nutraceutical

1. Introduction

The abrupt decrease of ovarian estrogen production at the menopause leads to vasomotor hot flashes, cognitive and emotional instability, sleep disturbance, urogenital atrophy and osteoporosis. Menopausal hormone therapy (MHT) with estradiol is the most effective treatment for menopausal complaints. However, many women prefer complementary or alternative remedies such as herbal preparations or nutraceuticals, which are perceived to be more natural than hormones and believed to be safer. This trend has increased after publications regarding increased breast cancer risk with combined estrogen/progestogen MHT. Soy extracts, containing the isoflavones diadzeïn and genisteïn [1] are effective against vasomotor complaints in some women [2]. Black cohosh (Cimicifuga racemosa) is commonly used, but concerns have been raised about possible liver toxicity [3] ;  [4].
This review aims at analyzing the evidence of possible effectiveness regarding menopausal symptoms and women's health of herbal preparations beyond soy isoflavones and black cohosh. It is based on publications from the last decade that were selected through PubMed.

1.1. Hop (Humulus lupulus)

Hop is a climbing plant of which the flower cones are an ingredient of many beers. The hop-flavonoid 8-prenylnaringenin (8-PN) is a stronger estrogen than soy isoflavones. There is some evidence that 8-PN may be efficacious against vasomotor complaints, but two RCT's regarding menopausal symptoms come to conflicting conclusions. Heyerick et al. [5] recorded a statistically significant benefit of 8-PN during the first 12 weeks of intake, remaining present after 12 weeks, though not significantly better than that of placebo. In contrast, Erkkola et al. [6] did not find a significant advantage of 8-PN over placebo in the first 16 weeks of treatment, while after this time period the difference became significant, as a result of the decreasing effect of placebo.
Prenylnaringenin reduces the malignant transformation of breast cancer cells in vitro, and the production of the oncogenic estrogen-O-quinone ( Fig. 1). However, the in vivo concentrations in breast tissue after daily oral intake of 100 μg per day may be insufficient to exert chemoprotection [7].
Estradiol (E2) and estrone (E1) are converted by the hydroxylase-enzymes into ...
Fig. 1. 
Estradiol (E2) and estrone (E1) are converted by the hydroxylase-enzymes into watersoluble hydroxy-estradiol/estrone. There are 3 different hydroxylases that act in the positions 2 or 4, or 16α of the estradiol/estrone molecules. The 16-α-hydroxy-estradiol/estrone (16α-OH-E1/E2) displays a strong estrogenic action, inducing cell division. These hydroxy-estrogens are considered genotoxic and cancerogenic. The 2- and 4-hydroxy-estrogens (2-OH-E1/E2, 4-OH-E1/E2) can be converted by the enzyme cathechol-O-methyltransferase (COMT) into inactive metabolites. Or they may be converted by cytochrome P450 or peroxidase into their respective S-quinones (the 2,3 S-quinone for the 2-hydroxy E1/E2, and the 3,4 S-quinone for the 4-hydroxy E1/E2). These S-quinones are both oxidized by a non-enzymatic reaction under the influence of reactive oxygen species (ROS) into their corresponding O-quinones. Both O-quinones can either be inactivated by the enzyme glutathione-S-transferase into glutathione conjugates, which are devoid of estrogenic activity. Both these O-quinones can also bind to DNA. The binding of 2,3-O-quinone to DNA generates stable adducts which carry no risk. The binding of the 3,4-O-quinone of estradiol or estrone to DNA cause depurination of particular DNA-nucleotides. The resulting derivatives can induce strand breaks and mutations in the daughter cells that may be cancerogenic.
Figure options

1.2. Vitex agnus-castus

The fruit-oil of Vitex agnus-castus binds to the estrogen receptor, inducing expression of estrogen-dependent genes, and it is commonly recommended for the treatment of premenstrual syndrome. This substance may exert dopaminergic action, but a favorable effect on menopausal symptoms has not been shown, even when combined with Hypericum perforatum (St John's wort) [8].

1.3. Dioscorea villosa

Diosgenin, the saponin extracted from the Dioscorea villosa (wild yam), does not bind to the human estrogen or progesterone receptor in vitro and cannot be converted in the human body to progesterone. Dioscorea could theoretically be given to women who have been treated for breast cancer, but safety data are required. When given as a cream, the effect on menopausal symptoms was not statistically significant compared to placebo [9]. Dioscorea was found to increase bone mineral density in ovariectomised rats [10], but studies in humans are lacking. A study where 22 women were given 390 g of yam per day for 30 days found that urinary concentrations of the genotoxic metabolite of estrogen, 16alpha-hydroxyestrone decreased significantly by 37% suggesting the potential to reduce breast cancer risk, but again clinical trial data are required [11] (Fig. 1).

1.4. Linseed or flaxseed (Linum usitatissimum)

Linseed extract is a major source of lignans that are metabolized by the intestinal flora into the weakly active estrogens enterodiol and enterolactone. In a RCT flaxseed meal and flaxseed extract were found to be significantly, albeit moderately, effective against menopausal symptoms [12]. Linseed extract increases the 2OH/16OH-estrogen ratio in urine to a greater extent than soy isoflavones [13]. It also inhibits intracellular aromatase activity, with less estradiol being produced from the precursors testosterone and dehydroepiandrosterone. Because of these effects, several publications have suggested that the intake of linseed extracts may protect against hormone-dependent breast cancer [14]. However, this could not be confirmed in a recent population study [15] and a prospective cohort study reported that postmenopausal breast cancer patients with high estimated enterolignans may have a better survival [16].
Dietary lignans may have the potential to protect against cardiovascular risk but evidence in large clinical trials is required.

1.5. Maritime pine bark extract

The extract of (Mediterranean) pine bark (Pycnogenol®) is a rich source of anthocyanidins, which are strong anti-oxidants, and reduce inflammation by inhibiting both cyclo-oxygenase 1 and 2 (COX 1&2), and nuclear factor kappa B (NF-kB) [17]. In three independent trials Pycnogenol® was found to significantly reduce vasomotor symptoms, and to improve the quality of life of menopausal women compared to placebo or no treatment [18]; [19] ;  [20]. The pine bark extract was also reported to improve endothelial function patients with coronary artery disease by reducing oxidative stress [21].

1.6. Cruciferous vegetables

Indole-3-carbinol is produced by the breakdown of the glucosinolate glucobrassicin, which can be found at relatively high levels in cruciferous vegetables such as Broccoli, cabbage and brussel sprouts. Two trials have suggested a potential role in vulvar and cervical intraepithelial neoplasia [22] ;  [23].
Also, Broccoli extract contains phylloquinone (vitamin K(1)) which has been reported to increase bone mineral density in postmenopausal women [24] and to slow the progression of coronary artery calcium deposits (CAC) in healthy older adults with preexisting CAC [25]. However there is no evidence that cruciferous vegetables improve menopausal symptoms.

1.7. Lepidium meyenii (Maca)

Maca (Lepidium meyenii), an Andean plant of the brassica (mustard) family has been used for centuries in the Andes to manage anemia, infertility and female hormone balance. A systematic review found four RCTs that met all inclusion criteria. These RCTs tested the effects of Maca on menopausal symptoms in healthy perimenopausal, early postmenopausal, and late postmenopausal women. Using the Kupperman Menopausal Index and the Greene Climacteric Score, all RCTs demonstrated favorable effects of Maca. However, the authors concluded that the total number of trials, the total sample size, and the average methodological quality of the primary studies, were too limited to draw firm conclusions. Furthermore, the safety has not yet been proven [26].

2. Summary

Complementary and alternative remedies using herbal medicines have a limited place in the treatment of menopausal complaints. They are used by women who are reluctant or anxious to use estradiol, but are not as effective as estrogen. Several plant extracts can alleviate vasomotor symptoms but not all are superior to placebo. Their potential beneficial effect in preventing osteoporosis remains to be proven. Some plant extracts may have the potential to reduce the risk of gynecological cancers and cardiovascular disease, but this needs evaluation in large clinical trials. Safety needs to be assessed particularly regarding potential herb–drug interactions.

3. Practice points

•
The extracts of Maritime pine bark, Maca, and flaxseed may improve vasomotor hot flashes but more clinical trials are required to draw firm conclusions.
•
In animal studies wild yam may protect against osteoporosis, but clinical trials in humans are required.
•
The effects on breast and gynecological cancer and cardiovascular disease need evaluation in clinical trials.

4. Research agenda

•
There is a need for long-term follow-up studies, either cohort or randomized trials, assessing the alleged health benefits of individual herbal preparations, or combinations of these.
•
Safety data and herb–drug/herb–herb interactions need evaluation.

Contributors

Both authors have contributed equally to this manuscript.

Competing interests

No competing interests.

Funding

No funding.

Provenance and peer review

Not commissioned, externally peer reviewed.

References

    • [3]
    • Medicines and Healthcare products Regulatory Agency (MHRA)
    • Liver failure case highlights need to use Black Cohosh remedies carefully
    • MHRA press (2012) press.office@mhra.psi.gov.uk

    • [4]
    • W. Peng, J. Adams, D.W. Sibbritt, J.E. Frawley
    • Critical review of complementary and alternative medicine use in menopause: focus on prevalence, motivation, decisionmaking, and communication
    • Menopause (2013) PMID: 24104604 [Epub ahead of print]

    • [5]
    • A. Heyerick, S. Vervarcke, H. Depypere, M. Bracke, D. De Keukeleire
    • A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts
    • Maturitas, 54 (2006), pp. 164–175
    • Article
      |
       PDF (419 K)
      |
      View Record in Scopus
       | 
      Citing articles (91)
    • [6]
    • R. Erkkola, S. Vervarcke, S. Vansteelandt, P. Rompotti, D. De Keukeleire, A. Heyerick
    • A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts
    • Phytomedicine, 17 (2010), pp. 389–396
    • Article
      |
       PDF (508 K)
      |
      View Record in Scopus
       | 
      Citing articles (37)
    • [8]
    • E. Laakmann, D. Grajecki, K. Doege, C. zu Eulenburg, K.J. Buhling
    • Efficacy of Cimicifuga racemosa, Hypericum perforatum and Agnus castus in the treatment of climacteric complaints: a systematic review
    • Gynecol Endocrinol, 28 (2012), pp. 703–709
    • CrossRef
      |
      View Record in Scopus
       | 
      Citing articles (16)
    • [13]
    • J.D. Brooks, W.E. Ward, J.E. Lewis, et al.
    • Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy
    • Am J Clin Nutr, 79 (2004), pp. 318–325
    • View Record in Scopus
       | 
      Citing articles (84)
    • [14]
    • E. Sonestedt, M.I. Ivarsson, S. Harlid, et al.
    • The protective association of high plasma enterolactone with breast cancer is reasonably robust in women with polymorphisms in the estrogen receptor alpha and beta genes
    • J Nutr, 139 (2009), pp. 993–1001
    • CrossRef
      |
      View Record in Scopus
       | 
      Citing articles (25)
    • [15]
    • R. Zamora-Ros, P. Ferrari, C.A. Gonzàles
    • Dietary flavonoid and lignan intake and breast cancer risk according to menopause and hormone receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study
    • Breast Cancer Res Treat (2013) [Epub ahead of print]

    • [16]
    • K. Buck, A.K. Zaineddin, A. Vrieling, et al.
    • Estimated enterolignans, lignan-rich foods, and fibre in relation to survival after postmenopausal breast cancer
    • Br J Cancer, 105 (2011), pp. 1151–1157
    • CrossRef
      |
      View Record in Scopus
       | 
      Citing articles (24)
    • [18]
    • H.M. Yang, M.F. Liao, S.Y. Zhu, M.N. Liao, P. Rohdewald
    • A randomized, double-blind, placebo-controlled trial on the effect of Pycnogenol on the climacteric syndrome in peri-menopausal women
    • Acta Obstet Gynecol Scand, 86 (2007), pp. 978–985
    • CrossRef
      |
      View Record in Scopus
       | 
      Citing articles (31)
    • [24]
    • G. Moschonis, S. Kanellakis, N. Papaioannou, A. Schaafsma, Y. Manios
    • Possible site-effect of an intervention combining nutrition and lifestyle counselling with consumption of fortified dairy products on bone mass: the Postmenopausal Health Study II
    • J Bone Miner Metab, 29 (2011), pp. 501–506
    • CrossRef
      |
      View Record in Scopus
       | 
      Citing articles (7)

Corresponding author. Tel.: +32 93323776; fax: +32 93770176.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Posted by at