Botanicals and Their Bioactive Phytochemicals for Women's Health

Abstract

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.

Fig. 1.

Botanicals women take as a function of age. The popularity of botanical dietary supplements varies as a function of age, hormone levels, and usage.

Fig. 2.

Structures of estradiol and progesterone.

Fig. 3.

Examples of prescription drugs used to treat premenstrual syndrome.

Fig. 4.

Examples of prescription drugs used to treat UTIs.

Fig. 5.

Examples of prescription drugs used to treat morning sickness or possible miscarriages.

Fig. 6.

Examples of prescription drugs used to increase milk production (galactagogues).

Fig. 7.

Examples of prescription drugs used for menopausal symptoms.

Fig. 8.

Integration of phytochemistry, bioassay, and pharmacokinetics to standardize botanicals to bioactive phytochemicals.

Fig. 9.

Phytochemicals in black cohosh.

Fig. 10.

Phytochemicals in dong quai.

Fig. 11.

Example of bioassay guided fractionation using black cohosh modified from Powell et al., 2008.

Fig. 12.

The UIC/NIH Center for Botanical Dietary Supplements Research: Interaction of projects and cores.

Fig. 13.

Phytochemicals in chasteberry.

Fig. 14.

Phytochemical in cramp bark and black haw.

Fig. 15.

Phytochemicals in ginger and their metabolites.

Fig. 16.

Phytochemical in valerian.

Fig. 17.

Phytochemicals in evening primrose.

Fig. 18.

Phytochemicals in cranberry.

Fig. 19.

Phytochemical in bearberry and its metabolites.

Fig. 20.

Phytochemicals in fenugreek.

Fig. 21.

Phytochemicals in milk thistle.

Fig. 22.

Serotonergic mechanism. In synapses, botanicals can directly act on the serotonin receptors (5-HT receptors) or reduce serotonin reuptake through inhibiting serotonin transporters (SERTs) to elicit a reduction in menopausal symptoms such as hot flashes.

Fig. 23.

Hormonal pathway. ERα and ERβ are activated by estrogens or phytoestrogens that cause dimerization of these receptors and translocation to the nucleus. Activation of ERE-responsive genes by ERα increases proliferation yet reduces menopausal symptoms and osteoporosis. On the other hand, ERβ decreases proliferation, while also decreasing menopausal symptoms and osteoporosis. Additionally, many botanicals reportedly decrease aromatase expression/activity to reduce synthesis of estrogen. This figure was simplified to represent only the classic estrogen signaling pathway.

Fig. 24.

Isoflavones in red clover, soy, and kudzu. Genistein and daidzein are both found in soy and red clover; however, they are significantly more abundant in soy. Daidzein is metabolized by the intestinal microflora to S-equol.

Fig. 25.

Isoflavone in guinea-bissau.

Fig. 26.

Phytochemicals in hops.

Fig. 27.

Phytochemicals in licorice.

Fig. 28.

Phytochemicals in rhubarb and their metabolites.

Fig. 29.

Phytochemicals in flaxseed.

Fig. 30.

Phytochemicals in horny goat weed.

Fig. 31.

Phytochemicals in maca.

Fig. 32.

Phytochemical in alfalfa.

Fig. 33.

Multitargeted modulation of estrogen carcinogenesis by botanicals. Estrogen carcinogenesis involves numerous pathways: (1) Hormonal (Fig. 23); estrogen binds to ERα, which activates EREs to increase proliferation. (2) Chemical (Figs. 34, 35); the aryl hydrocarbon receptor (AhR) is activated by AhR agonists, which increases P450 1A1 (benign pathway) and P450 1B1 (genotoxic pathway). Additionally, Nrf2-secondMaf binding to the antioxidant response element (ARE) increases NQO1 and phase II enzymes that detoxify genotoxic estrogen o-quinones, which initiate genotoxicity through DNA adducts and ROS produced from redox cycling between the catechol and estrogen-o-quinones. (3) Inflammatory (Fig. 36); inflammatory biomarkers, such as cytokines, increase aromatase expression, thus, increasing estrogen and feeding both the chemical and hormonal pathway. Cytokines, derived from chronic inflammation, macrophages or adipocytes, reportedly suppress P450 1A1, yet increase P450 1B1, most likely through the inflammatory mediator NF-κB. Cytokines also increase expression of genes (i.e., NF-κB, iNOS, COX-2) in epithelial and malignant cells that are often overexpressed in breast cancer patients. (4) Epigenetic (Fig. 37); epigenetic events through ERα inhibit expression of P450 1A1 by encouraging hypermethylation of its promoter, whereas having no significant effect on P450 1B1 expression. Green arrows represent potential positive effects of botanicals, whereas red arrows represent negative effects in each pathway.

Fig. 34.

Estrogen chemical carcinogenesis. AhR ligands activate XRE-responsive genes, P450 1A1 and P450 1B1, to increase benign and genotoxic estrogen metabolism, respectively. ERα decreases P450 1A1 expression by encouraging DNA methylation of the promoter and inflammatory cytokines that activate NF-κB decrease P450 1A1, yet increase P450 1B1. AhR modulating, estrogenic, anti-inflammatory, and antioxidant botanicals may modulate estrogen chemical carcinogenesis by targeting AhR, ERα, and reducing inflammatory cytokines and NF-κB activation. Botanicals might also increase detoxification of estrogens through activating the Keap1-Nrf2-ARE pathway, thus increasing NQO1 and other detoxification enzymes.

Fig. 35.

Nrf2 pathway. Under normal conditions Nrf2 is associated with Keap1 in the cytosol and ubiquitinated by Cul3, causing Nrf2 proteasomal degradation. Electrophilic botanicals covalently modify cysteines in Keap1, leading to a conformational change; inhibition of Cul3-mediated Nrf2 ubiquitination, accumulation, and nuclear translocation of Nrf2; and upregulation of ARE-regulated detoxification enzymes.

Fig. 36.

Inflammatory pathway. Many botanicals are anti-inflammatory, inhibiting production of inflammatory biomarkers that are often overexpressed in breast cancer (i.e., cytokines, iNOS and COX-2). Electrophilic botanicals covalently modify both IKK and NF-κB to inhibit phosphorylation and DNA binding, respectively. Many phytochemicals also inhibit COX-2 and thus the production of PGE2.

Fig. 37.

Epigenetic pathway. Simplified overview of botanicals modulating epigenetic enzymes, resulting in modulation of estrogen metabolizing enzymes and tumor suppressors. HMT, histone methyltransferases; HDM, histone demethyltransferases; HAT, histone acetyltransferases; HDAC, histone deacetylases; DNMT, DNA methyltransferases.

Fig. 38.

(A) Coumarin derivative present in dong quai; (B) warfarin, anticoagulant drug.

Fig. 39.

Multiple biological effects of women’s health botanicals. Women’s botanical dietary supplements are complex mixtures of bioactive compounds that interact with multiple pharmacological targets. Estrogenic botanicals that specifically target ERβ might decrease cell proliferation in addition to their effect on menopausal symptoms and osteoporosis. Serotonergic botanicals may reduce menopausal symptoms by targeting the serotonin receptor (5-HT receptors) or inhibiting serotonin reuptake. Women mainly use antimicrobial botanicals for remedying UTIs and antispasmodic drugs to remedy PMS symptoms. Chemopreventive botanicals target several biomolecules within four major pathways: (1) hormonal (ER, aromatase); (2) chemical (i.e., AhR, Keap1-Nrf2, ROS); (3) inflammatory (i.e., NF-κB, COX-2); and (4) epigenetic (i.e., HDACs, HMT, HATs). However, toxicity has been observed with botanicals that may increase overall cellular toxicity and interfere with activities of prescription medication. Green arrows indicate hypothesized beneficial biological effects.