538 Reviews Botanical Modulation of Menopausal Symptoms: Mechanisms of Action? Authors Atieh Hajirahimkhan, Birgit M. Dietz, Judy L. Bolton Affiliation UIC/NIH Center for Botanical Dietary Supplements, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA Key words Abstract cacious formulations and to the isolation of active l" botanicals ! components which have the potential of becom- l" estrogen Menopausal women suffer from a variety of ing effective medications in the future. l" isoflavones symptoms, including hot flashes and night l" menopause sweats, which can affect quality of life. Although l" progesterone l" serotonin it has been the treatment of choice for relieving Abbreviations these symptoms, hormone therapy has been as- ! sociated with increased breast cancer risk leading AP-1: activator protein 1 many women to search for natural, efficacious, E2:17β-estradiol and safe alternatives such as botanical supple- ER: estrogen receptor ments. Data from clinical trials suggesting that ERE: estrogen responsive element botanicals have efficacy for menopausal symptom GPER: G-protein coupled estrogen receptor relief have been controversial, and several mecha- GPR30: G-protein coupled estrogen receptor nisms of action have been proposed including es- subtype 30 trogenic, progestogenic, and serotonergic path- HT: hormone therapy ways. Plant extracts with potential estrogenic ac- 5-HT: 5-hydroxytryptamine (serotonin) tivities include soy, red clover, kudzu, hops, lico- 5-HT7: 5-hydroxytryptamine receptor 7 rice, rhubarb, yam, and chasteberry. Botanicals MAPKs: mitogen-activated protein kinases with reported progestogenic activities are red PI3K: phosphatidylinositol 3-kinase clover, hops, yam, and chasteberry. Serotonergic 8-PN 8-prenylnaringenin mechanisms have also been proposed since wom- P4: progesterone en taking antidepressants often report a reduc- PR: progesterone receptor received July 20, 2012 tion in hot flashes and night sweats. Black cohosh, PRE: progesterone responsive element revised Nov. 28, 2012 accepted January 4, 2013 kudzu, kava, licorice, and dong quai all either have SERT: serotonin transporter reported 5-hydroxytryptamine receptor 7 ligands SSRI: selective serotonin reuptake Bibliography or inhibit serotonin reuptake, therefore have po- inhibitor DOI http://dx.doi.org/ tential serotonergic activities. Understanding the WHI: Womenʼs Health Initiative This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 10.1055/s-0032-1328187 Published online February 13, mechanisms of action of these natural remedies 2013 used for womenʼs health could lead to more effi- Planta Med 2013; 79: 538–553 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0032‑0943 Introduction menopausal symptoms, traditional HT (estrogen ! or estrogen plus progestin), was designed to sup- Correspondence Women potentially spend the last third of their plement the hormones. However, the WHI dem- Prof. Dr. Judy Bolton Department of Medicinal lives in postmenopause, due to their increased life onstrated an increased risk of developing breast Chemistry and Pharmacognosy expectancy. Menopausal women suffer from a va- cancer associated with HT [4] leading women to College of Pharmacy, University riety of symptoms, such as hot flashes, night search for natural alternatives such as botanical of Illinois at Chicago 833 South Wood St. M/C 781 sweats, mood swings, insomnia, vaginal dryness, supplements [5,6]. Chicago IL 60612–7231 in addition to long-term complications such as os- Botanicals, which are generally perceived as safe USA teoporosis [1,2]. These symptoms arise primarily due to their natural origin, have a long history of Phone: + 13129965280 Fax: + 13129967107 as a response to the drastic decline in circulating use for female complaints, particularly in tradi- [email protected] endogenous estrogens [3]. In order to relieve tional Chinese medicine [7]. The fact that Asian Hajirahimkhan A et al. Botanical Modulation of… Planta Med 2013; 79: 538–553 Reviews 539 Fig. 2 Mechanism of serotonergic activity. Serotonin is released in the synapses and binds to its receptor (5-HT7) in the post-synaptic cells. A serotonin recep- tor, coupled with a G- protein, activates ade- nylate cyclase, resulting in production of cAMP and activation of enzy- matic cascades leading to serotonergic effects. Fig. 1 Classical mechanisms of the estrogenic and progestogenic activ- ities. women have less frequent and severe hot flashes suggests that effects of estrogens, while ERβ activation balances the ERα-de- this effect could be associated with their flavonoid-rich diet and pendent responses [27–29]. that botanicals with high flavonoid content could be effective in Botanicals and specifically their phytoestrogens, such as genis- managing menopausal symptoms [8]. As a result, many women tein and daidzein, preferentially bind and activate ERβ, thus may turn to botanical dietary supplements for alleviation of meno- exert a safe estrogenic activity [15,30]. However, the use of bo- pausal symptoms, specifically for the reduction of hot flashes [5, tanicals with only plant-derived estrogens in the absence of pro- 6]. gestins might increase the risk of developing endometrial hyper- Botanical supplements could act through a number of different plasia and cancer similar to conventional estrogen-alone HT [31, mechanisms including estrogenic, progestogenic, and/or seroto- 32]. It is known that women with an intact uterus who take HT to nergic pathways (l" Figs. 1 and 2)[9–13]. It is thought that botan- treat estrogen-deficient menopausal symptoms must take a com- icals with estrogenic activity might mimic the actions of estro- bination of estrogens and progestins, and the same is likely true gens. The importance of estrogen in homeostatic regulation of for phytoestrogens and phytoprogestins. P4, the precursor of many cellular and biochemical events is well illustrated by the many steroid hormones, plays a crucial role in the normal physi- pathophysiological changes that occur with estrogen deficiency ology of the uterus, ovaries, mammary gland, cardiovascular sys- [14–17]. Endogenous estrogen (estradiol, E2) is actively involved tem, bone, brain, and central nervous system [33]. Its biological in the development of the mammary gland and uterus, in main- function is mainly mediated through its binding to PRs, including taining pregnancy and bone density, in protection from cardio- PRA and PRB, followed by the receptor dimerization, transloca- vascular diseases, and in relieving menopausal symptoms [16– tion to the nucleus, and interaction with PREs, thus regulating 19]. Estrogens mainly exert their biological effects through bind- transcription of downstream genes (l" Fig. 1) [34]. Animal models ing to ERs including ERα and ERβ, followed by dimerization of ERs partially suggest that PRA induction is protective in the uterus, and interaction with EREs at the promoter of the estrogen re- while PRB induction might increase breast proliferation [35–37]. sponsive genes, thus activating transcription and generating es- Botanicals containing natural progestins, which can activate pro- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. trogenic responses which are crucial for normal physiological gesterone-dependent pathways, in addition to estrogenic com- functions (l" Fig. 1)[20–22]. In humans around one-third of the pounds are preferred. genes that are regulated by ERs do not contain ERE-like se- Estrogen withdrawal during menopause results in the decline in quences [22,23]. ERs can also tether to other transcription factors the release of neurotransmitters, primarily norepinephrine and such as Fos and Jun that are directly bound to DNA through their serotonin (5-HT), which will lead to a change in thermoregula- respective responsive elements such as AP1 binding sites to reg- tion in the hypothalamus [38]. This effect ultimately results in ulate transcription of the related genes [22,23]. Estrogen also ac- frequent sweating and increased peripheral circulation as heat- tivates rapid signaling pathways such as MAPKs and PI3K path- loss mechanisms generating hot flashes and night sweats. In- ways, which, in turn, can modulate transcription and prolifera- crease in the amount of serotonin and activation of certain 5-HT tion [22,24]. Studies have revealed another type of ER, namely receptors as well as inhibition of serotonin reuptake in synapses GPER or GPR30, that is involved in different signaling pathways through the blocking of SERTs are possible approaches in pre- " [25,26]. It is also known that mechanisms of E2 actions depend venting hot flashes (l Fig. 2). In order to avoid hormonal ap- on the ligand, the cell type, and the receptor subtype [22,23]. It proaches, some women choose SSRIs to manage menopausal dis- is believed that ERα induction is responsible for the proliferative comforts, particularly vasomotor symptoms [39]. However, there are also a number of undesirable outcomes such as sexual dys- Hajirahimkhan A et al. Botanical Modulation of… Planta Med 2013; 79: 538–553 540 Reviews Table 1 Estrogenic potency of phytoestrogens in competitive ER binding assaya. b Compound Plant References IC50 (µM) reported range ER binding ERα ERβ 17β-estradiol (E2) – [89, 101,185] 0.00 001–0.003 0.0014–0.0038 Genistein soy, red clover, kudzu [50, 101,185] 0.59–1.145 0.025–0.09 Daidzein soy, red clover, kudzu