View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector J Acupunct Meridian Stud 2016;9(3):109e117 Available online at www.sciencedirect.com Journal of Acupuncture and Meridian Studies journal homepage: www.jams-kpi.com REVIEW ARTICLE Compounds of Natural Origin and Acupuncture for the Treatment of Diseases Caused by Estrogen Deficiency Abhishek Thakur 1, Subhash C. Mandal 2, Sugato Banerjee 1,* 1 Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India 2 Division of Pharmacognosy, Pharmacognosy and Phytotherapy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India Available online 17 February 2016 Received: Sep 2, 2015 Abstract Revised: Jan 24, 2016 A predominant number of diseases affecting women are related to female hormones. In Accepted: Jan 28, 2016 most of the cases, these diseases are reported to be associated with menstrual problems. These diseases affect female reproductive organs such as the breast, uterus, and ovaries. KEYWORDS Estrogen is the main hormone responsible for the menstrual cycle, so irregular menstru- acupuncture; ation is primarily due to a disturbance in estrogen levels. Estrogen imbalance leads to estrogen; various pathological conditions in premenopausal women, such as endometriosis, breast natural compounds cancer, colorectal cancer, prostate cancer, poly cysts, intrahepatic cholestasis of preg- nancy, osteoporosis, cardiovascular diseases, obesity, etc. In this review, we discuss com- mon drug targets and therapeutic strategies, including acupuncture and compounds of natural origin, for the treatment of diseases caused by estrogen deficiency. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any me- dium, provided the original work is properly cited. * Corresponding author. Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India. E-mail: [email protected] (S. Banerjee). pISSN 2005-2901 eISSN 2093-8152 http://dx.doi.org/10.1016/j.jams.2016.01.016 Copyright ª 2016, Medical Association of Pharmacopuncture Institute. 110 A. Thakur et al. 1. Introduction cardiovascular diseases, insulin resistance, and obesity [6,10]. Estrogen is also considered to be a morphogen for Estrogen, the primary female hormone, is synthesized in the uterus, ovary, mammary gland, prostate, lung, and the theca interna of the female ovary and varies throughout brain [11]. Recurrence in breast cancer after mastectomy the menstrual cycle. Follicle-stimulating hormone (FSH) and recurrence of endometriosis after total hysterectomy e also stimulates the production of estrogens by the gran- are not uncommon [12 14]. In such cancerous conditions, ulosa cells of the ovarian follicles and corpora lutea [1,2]. estrogen deprivation becomes a key therapeutic approach Estrogens are also synthesized in small amount in the [15]. breast, liver, adrenal glands, and fat cells. Estrogen is found to be at its highest level at the end of the follicular phase in a menstrual cycle, just before ovulation [3].It 2. Common drug targets in estrogen- promotes secondary sexual characters in females, such as dependent conditions breast development, and also helps maintain the thickening of the endometrium and prepares the uterine lining for Aromatase enzyme is responsible for the synthesis of es- implantation of the fertilized ovary [4,5]. Such estrogen trogens through conversion of androgens into estrogens by a dominance can start early in a woman’s menstrual history. process called aromatization [14,15]. This leads to an in- Long-term exposure to estrogen has been associated with crease in the rate of production of estrogen, which pro- the development of breast cancer. Estrogen may contribute motes estrogen-dependent diseases. This enzyme is to the development of cancer in an estrogen receptor (ER)- expressed in high concentrations in the placenta and the dependent or ER-independent manner [6,7]. The ER- granular cells of ovarian follicles. This enzyme is also pre- dependent mechanism states that estrogen primarily acts sent in several nonglandular tissues such as endometrial on ER alpha, which is a transcription factor and mediates tissue, breast cancer tissue, normal breast tissue, subcu- DNA synthesis and cellular proliferation. While some cells taneous fat, muscle, liver, and brain [16]. It is an anticancer may use different mechanisms to metabolize and deacti- target by compounds inhibiting the action of the enzyme in vate different estrogens (estradiol and estrone) resulting in postmenopausal women [13,17,18]. Estrogen-dependent the generation of an intermediate reactive oxygen species, diseases can be treated more effectively with new third- which may damage DNA and eventually lead to cancer [8]. generation aromatase inhibitors. The third-generation Aromatase, which may be localized in breast cancer aromatase inhibitors are available in preparations such as tissue, endometriosis, and uterine fibroids, is responsible letrozole, anastrazole, vorazole, etc. [17,19]. Letrozole is for converting androgens (androstenedione and testos- considered to be the most promising aromatase inhibitor, as terone) into estrogens (estrone and estradiol), and for it has been studied that patients on letrozole have lower promoting cancerous growth and proliferation [8,9]. These plasma estrogen levels than those on other third-generation conditions may be dependent on the rising and falling of agents [20] (Fig. 1). estrogen waves during each menstrual cycle [6]. Estrogen is ER antagonists bind to ERs and inhibit the action of es- a hormone whose imbalance is responsible not only for trogen. ERs are available as homodimers of alpha and beta reproductive disorders, but also for different types of subunits (Fig. 2). ER alpha antagonist has shown resistance cancer. It may also contribute toward the development of in treating estrogen-dependent cancer for a prolonged lupus erythematosus, osteoporosis, Alzheimer’s disease, period of time [21]. Recent studies provide an important Figure 1 Androgen bound to enzyme aromatase at its active binding site. Natural Estrogen Modulators 111 Figure 2 Estrogen bound to estrogen receptor a at its active binding site. interface to study the role of ER beta for estrogen- shown to interact with ERs. AhR may inhibit estrogen dependent tumors [22]. Among these estrogen antago- signaling by the activation of AhR/aryl hydrocarbon nuclear nists, ethinyl estradiol is used in preparations such as ovral- translocator heterodimer; by binding to an inhibitory L and novelon. Compounds of natural origin include xenobiotic response element in ER target genes; by genistein, which may act on both ER alpha and ER beta silencing coactivators, i.e., aryl hydrocarbon nuclear (Fig. 3). Commonly used drugs in this patient subgroup are translocator; by increasing proteasomal degradation of ER; clomifene and zuclomifene, which have found greater and by altering estrogen synthesis or metabolism [24]. acceptance [23]. Clomifene and zuclomifene are widely Several natural and synthetic agonists have been identified used estrogen antagonists that may control estrogen levels for this receptor. The first agonist to be identified was a during menstrual cycle. synthetic one; thereafter, many natural ligands were Aryl hydrocarbon receptor (AhR) is a ligand-mediated identified, including tryptophan, tetrapyrroles, and arach- transcription factor [24]. The AhR pathway has been idonic acid [25]. Although the role of natural compounds Figure 3 Natural estrogen modulator (genistein) bound to estrogen receptor a at its active binding site. 112 Table 1 Natural estrogen modulators. 1. Genistein Glycine max Isoflavone Genistein may act by binding to estrogen receptors (a & b). [36] 2. Daidzein G. max Daidzein competes with endogenous estrogens binding with [38] 3. Equol G. max human recombinant estrogen receptor b & consequently [36] prevent their activity. 4. Luteolin Terminalia chebula Flavone Luteolin competes with endogenous estrogens binding with [36] human recombinant estrogen receptor b & consequently prevent their activity. 5. Chrysin Passiflora caerulea, Passiflora Chrysin performs potent inhibition of aromatase with [38] incarnata, Oroxylum indicum IC50 of 2.6 mM. 6. Quercetin Various fruits, vegetables, & grains Quercetin interacts with Type II estrogen-binding sites & inhibits [39] cell proliferation. 7. Kaempferol Apples, grapefruit, tea These have been found to bind weakly to the human recombinant [37] estrogen receptor b, thus preventing cell proliferation 8. Apigenin Various fruits & vegetables High doses of apigenin block ERa mobility & transcriptional activity, [43] & induce degradation of ERa & its coactivator AIB1. However, it may act via ERa-independent pathway as a kinase inhibitor. 9. 8-Prenyl Humulus lupulus Prenyl It has been shown to reduce hot flushes by binding to both ERa [40,41] naringenin flavonoid &ERb, but have higher affinity for ERa. 10. Naringenin Citrus paradisi Flavanone Studies have shown estrogen antagonist activity of this drug for [42] estrogen-sensitive cells. Have higher binding affinity for ERb than for ERa. 11. Enterodiol They are classified as mammalian Lignan Enterodiol acts as a protective agent for breast & prostate