Botanical dietary supplements are increasingly popular for women’s health, particularly for older women. The specific botanicals women take vary as a function of age. Younger women will use botanicals for urinary tract infections, especially Vaccinium macrocarpon (cranberry), where there is evidence for efficacy. Botanical dietary supplements for premenstrual syndrome (PMS) are less commonly used, and rigorous clinical trials have not been done. Some examples include Vitex agnus-castus (chasteberry), Angelica sinensis (dong quai), Viburnum opulus/prunifolium (cramp bark and black haw), and Zingiber officinale (ginger). Pregnant women have also used ginger for relief from nausea. Natural galactagogues for lactating women include Trigonella foenum-graecum (fenugreek) and Silybum marianum (milk thistle); however, rigorous safety and efficacy studies are lacking. Older women suffering menopausal symptoms are increasingly likely to use botanicals, especially since the Women’s Health Initiative showed an increased risk for breast cancer associated with traditional hormone therapy. Serotonergic mechanisms similar to antidepressants have been proposed for Actaea/Cimicifuga racemosa (black cohosh) and Valeriana officinalis (valerian). Plant extracts with estrogenic activities for menopausal symptom relief include Glycine max (soy), Trifolium pratense (red clover), Pueraria lobata (kudzu), Humulus lupulus (hops), Glycyrrhiza species (licorice), Rheum rhaponticum (rhubarb), Vitex agnus-castus (chasteberry), Linum usitatissimum (flaxseed), Epimedium species (herba Epimedii, horny goat weed), and Medicago sativa (alfalfa). Some of the estrogenic botanicals have also been shown to have protective effects against osteoporosis. Several of these botanicals could have additional breast cancer preventive effects linked to hormonal, chemical, inflammatory, and/or epigenetic pathways. Finally, although botanicals are perceived as natural safe remedies, it is important for women and their healthcare providers to realize that they have not been rigorously tested for potential toxic effects and/or drug/botanical interactions. Understanding the mechanism of action of these supplements used for women’s health will ultimately lead to standardized botanical products with higher efficacy, safety, and chemopreventive properties.

The increased cancer risk associated with hormone therapies has encouraged many women to seek non-hormonal alternatives including botanical supplements such as hops (Humulus lupulus) and licorice (Glycyrrhiza spec.) to manage menopausal symptoms. Previous studies have shown estrogenic properties for hops, likely due to the presence of 8-prenylnarigenin, and chemopreventive effects mainly attributed to xanthohumol. Similarly, a combination of estrogenic and chemopreventive properties has been reported for various Glycyrrhiza species. The major goal of the current study was to evaluate the potential estrogenic effects of three licorice species (Glycyrrhiza glabra, G. uralensis, and G. inflata) in comparison with hops. Extracts of Glycyrrhiza species and spent hops induced estrogen responsive alkaline phosphatase activity in endometrial cancer cells, estrogen responsive element (ERE)-luciferase in MCF-7 cells, and Tff1 mRNA in T47D cells. The estrogenic activity decreased in the order H. lupulus > G. uralensis > G. inflata > G. glabra. Liquiritigenin was found to be the principle phytoestrogen of the licorice extracts; however, it exhibited lower estrogenic effects compared to 8-prenylnaringenin in functional assays. Isoliquiritigenin, the precursor chalcone of liquiritigenin, demonstrated significant estrogenic activities while xanthohumol, a metabolic precursor of 8-prenylnaringenin, was not estrogenic. Liquiritigenin showed ERβ selectivity in competitive binding assay and isoliquiritigenin was equipotent for ER subtypes. The estrogenic activity of isoliquiritigenin could be the result of its cyclization to liquiritigenin under physiological conditions. 8-Prenylnaringenin had nanomolar estrogenic potency without ER selectivity while xanthohumol did not bind ERs. These data demonstrated that Glycyrrhiza species with different contents of liquiritigenin have various levels of estrogenic activities, suggesting the importance of precise labeling of botanical supplements. Although hops shows strong estrogenic properties via ERα, licorice might have different estrogenic activities due to its ERβ selectivity, partial estrogen agonist activity, and non-enzymatic conversion of isoliquiritigenin to liquiritigenin.

Botanical dietary supplements for women's health are increasingly popular. Older women tend to take botanical supplements such as hops as natural alternatives to traditional hormone therapy to relieve menopausal symptoms. Especially extracts from spent hops, the plant material remaining after beer brewing, are enriched in bioactive prenylated flavonoids that correlate with the health benefits of the plant. The chalcone xanthohumol (XH) is the major prenylated flavonoid in spent hops. Other less abundant but important bioactive prenylated flavonoids are isoxanthohumol (IX), 8-prenylnaringenin (8-PN), and 6-prenylnaringenin (6-PN). Pharmacokinetic studies revealed that these flavonoids are conjugated rapidly with glucuronic acid. XH also undergoes phase I metabolism in vivo to form IX, 8-PN, and 6-PN. Several hop constituents are responsible for distinct effects linked to multiple biological targets, including hormonal, metabolic, inflammatory, and epigenetic pathways. 8-PN is one of the most potent phytoestrogens and is responsible for hops' estrogenic activities. Hops also inhibit aromatase activity, which is linked to 8-PN. The weak electrophile, XH, can activate the Keap1-Nrf2 pathway and turn on the synthesis of detoxification enzymes such as NAD(P)H-quinone oxidoreductase 1 and glutathione S-transferase. XH also alkylates IKK and NF-κB, resulting in anti-inflammatory activity. Antiobesity activities have been described for XH and XH-rich hop extracts likely through activation of AMP-activated protein kinase signaling pathways. Hop extracts modulate the estrogen chemical carcinogenesis pathway by enhancing P450 1A1 detoxification. The mechanism appears to involve activation of the aryl hydrocarbon receptor (AhR) by the AhR agonist, 6-PN, leading to degradation of the estrogen receptor. Finally, prenylated phenols from hops are known inhibitors of P450 1A1/2; P450 1B1; and P450 2C8, 2C9, and 2C19. Understanding the biological targets of hop dietary supplements and their phytoconstituents will ultimately lead to standardized botanical products with higher efficacy, safety, and chemopreventive properties.