Compounds of Natural Origin and Acupuncture for the Treatment of Diseases Caused by Estrogen Deficiency

Abstract

A predominant number of diseases affecting women are related to female hormones. In 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. Estrogen is the main hormone responsible for the menstrual cycle, so irregular menstruation is primarily due to a disturbance in estrogen levels. Estrogen imbalance leads to various pathological conditions in premenopausal women, such as endometriosis, breast cancer, colorectal cancer, prostate cancer, poly cysts, intrahepatic cholestasis of pregnancy, osteoporosis, cardiovascular diseases, obesity, etc. In this review, we discuss common drug targets and therapeutic strategies, including acupuncture and compounds of natural origin, for the treatment of diseases caused by estrogen deficiency.

1. Introduction

Estrogen, the primary female hormone, is synthesized in the theca interna of the female ovary and varies throughout the menstrual cycle. Follicle-stimulating hormone (FSH) also stimulates the production of estrogens by the granulosa cells of the ovarian follicles and corpora lutea [1,2]. Estrogens are also synthesized in small amount in the 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 promotes secondary sexual characters in females, such as breast development, and also helps maintain the thickening of the endometrium and prepares the uterine lining for implantation of the fertilized ovary [4,5]. Such estrogen dominance can start early in a woman’s menstrual history. Long-term exposure to estrogen has been associated with the development of breast cancer. Estrogen may contribute to the development of cancer in an estrogen receptor (ER)-dependent or ER-independent manner [6,7]. The ER-dependent mechanism states that estrogen primarily acts on ER alpha, which is a transcription factor and mediates DNA synthesis and cellular proliferation. While some cells may use different mechanisms to metabolize and deactivate different estrogens (estradiol and estrone) resulting in the generation of an intermediate reactive oxygen species, which may damage DNA and eventually lead to cancer [8].

Aromatase, which may be localized in breast cancer tissue, endometriosis, and uterine fibroids, is responsible for converting androgens (androstenedione and testosterone) into estrogens (estrone and estradiol), and for promoting cancerous growth and proliferation [8,9]. These conditions may be dependent on the rising and falling of estrogen waves during each menstrual cycle [6]. Estrogen is a hormone whose imbalance is responsible not only for reproductive disorders, but also for different types of cancer. It may also contribute toward the development of lupus erythematosus, osteoporosis, Alzheimer’s disease, cardiovascular diseases, insulin resistance, and obesity [6,10]. Estrogen is also considered to be a morphogen for the uterus, ovary, mammary gland, prostate, lung, and brain [11]. Recurrence in breast cancer after mastectomy and recurrence of endometriosis after total hysterectomy are not uncommon [12–14]. In such cancerous conditions, estrogen deprivation becomes a key therapeutic approach [15].

2. Common drug targets in estrogen-dependent conditions

Aromatase enzyme is responsible for the synthesis of estrogens through conversion of androgens into estrogens by a process called aromatization [14,15]. This leads to an increase in the rate of production of estrogen, which promotes estrogen-dependent diseases. This enzyme is expressed in high concentrations in the placenta and the granular cells of ovarian follicles. This enzyme is also present in several nonglandular tissues such as endometrial tissue, breast cancer tissue, normal breast tissue, subcutaneous fat, muscle, liver, and brain [16]. It is an anticancer target by compounds inhibiting the action of the enzyme in postmenopausal women [13,17,18]. Estrogen-dependent diseases can be treated more effectively with new third-generation aromatase inhibitors. The third-generation aromatase inhibitors are available in preparations such as letrozole, anastrazole, vorazole, etc. [17,19]. Letrozole is considered to be the most promising aromatase inhibitor, as it has been studied that patients on letrozole have lower plasma estrogen levels than those on other third-generation agents [20] (Fig. 1).

Figure 1

Androgen bound to enzyme aromatase at its active binding site.

ER antagonists bind to ERs and inhibit the action of estrogen. ERs are available as homodimers of alpha and beta subunits (Fig. 2). ER alpha antagonist has shown resistance in treating estrogen-dependent cancer for a prolonged period of time [21]. Recent studies provide an important interface to study the role of ER beta for estrogen-dependent tumors [22]. Among these estrogen antagonists, ethinyl estradiol is used in preparations such as ovral-L and novelon. Compounds of natural origin include genistein, which may act on both ER alpha and ER beta (Fig. 3). Commonly used drugs in this patient subgroup are clomifene and zuclomifene, which have found greater acceptance [23]. Clomifene and zuclomifene are widely used estrogen antagonists that may control estrogen levels during menstrual cycle.

Figure 2

Estrogen bound to estrogen receptor a at its active binding site.

Figure 3

Natural estrogen modulator (genistein) bound to estrogen receptor α at its active binding site.

Aryl hydrocarbon receptor (AhR) is a ligand-mediated transcription factor [24]. The AhR pathway has been shown to interact with ERs. AhR may inhibit estrogen signaling by the activation of AhR/aryl hydrocarbon nuclear translocator heterodimer; by binding to an inhibitory xenobiotic response element in ER target genes; by silencing coactivators, i.e., aryl hydrocarbon nuclear translocator; by increasing proteasomal degradation of ER; and by altering estrogen synthesis or metabolism [24]. Several natural and synthetic agonists have been identified for this receptor. The first agonist to be identified was a synthetic one; thereafter, many natural ligands were identified, including tryptophan, tetrapyrroles, and arachidonic acid [25]. Although the role of natural compounds targeting estrogen-dependent diseases is unclear, in some studies phthalates have shown an interaction with ERs via AhR [26]. Studies have shown that people treated with drugs targeting estrogen-dependent diseases via AhR have less chance of developing osteoporosis [27]. Further studies on this receptor are needed, so that a potent AhR agonist can be formulated for targeting estrogen-dependent diseases [28].

3. Natural compounds as potential therapeutics

Flavonoids, primarily known for their antioxidant properties, have also shown antiestrogenic effect for the first time in sheep, which leads to infertility [29]. Some studies have shown that flavonoids may bind and activate ERs. Flavonoids have been classified into six classes: flavonols, flavones, flavanols, flavanonols, flavanones, and isoflavones [30]. Among all flavones, isoflavones have been shown to possess the highest antiestrogenic activity. Flavanones and flavones have been shown to possess better antiestrogenic activity as compared with flavans. Studies have shown the importance of 6, 7, or 4 hydroxy group in flavones for estrogenic activity [31].

Coumestanes are a class of natural phytoestrogen found in a variety of food sources, including peas, beans, sprouts, etc. Coumestanes have been shown to have antiestrogenic properties—they possess specific binding affinity for ER beta. To explore their antiestrogenic property, many chemical entities similar to coumestane class were synthesized and isolated. Among them coumesterol has shown more specific antiestrogenic affinity for ER beta [32].

Lignans, one of the important phytoestrogens obtained from dietary sources (flaxes and cereals), have been reported to possess antitumor activity against estrogen-dependent cancers. It is believed that lignans mimic estrogen and bind to ERs, thus preventing the action of endogenous estrogen. Moreover, studies also state that when phytoestrogens are consumed, the endogenous estrogen is flushed out of the body, adding to the anti-estrogenic activity of phytoestrogens [33,34].

Stilbenes are diarylethylene hydrocarbons existing in two possible isomers, cis and trans. Many stilbenoids are present in plants, and between the two isoforms, trans possess greater antiestrogenic activity. Many synthetic drugs such as diethylstilbestrol, fosfestrol, and dienestrol have been designed on the basis of the trans isoform. Some natural stilbenes include pterostilbene and resveratrol [35].

A list of estrogen-modulating natural compounds and their mechanisms of action are listed in Table 1, while their chemical structures are shown in Fig. 4.

Table 1 Natural estrogen modulators.

Figure 4

Structures of natural compounds with estrogen-modulating properties.

4. Acupuncture for estrogen-associated conditions

Premenopause and menopause may be associated with mood swings and minor memory deficit, which are associated with a low estrogen level. Although hormone replacement therapy may improve the condition up to a certain extent, there are other problems also [56]. Recent reports have shown certain acupuncture protocol may treat menopausal syndrome and subsequently improve memory [58,59]. The treatment is also claimed to alter plasma estradiol levels [57]. Acupuncture has also been shown to improve learning and memory by increasing brain estrogen levels in rats [58,59]. In a study comparing the effects of acupuncture and estrogen on the frequency of hot flushes suggest that electroacupuncture may significantly reduce the frequency of hot flushes. Although estrogen therapy may be more effective than acupuncture in reducing hot flushes, acupuncture therapy has limited side effects as compared with estrogen therapy [60]. Vasomotor symptoms are common among the group of women suffering from breast cancer who are undergoing antiestrogen therapy, so it becomes extremely difficult to treat such a group of patients. However, treatment of such a group of patients for vasomotor symptoms associated with antiestrogen therapy with acupuncture appears to be effective and safe [61]. Repeated electroacupuncture stimulation at some effective acupoints has also been reported to increase ER expression and enhance estrogen levels in ovariectomized animals, thus suggesting a long-term increase and normalization of Hypothalamic-pituitary-adrenal (HPA) axis dysfunction [62,63].

Patients on acupuncture therapy showed decreased levels of FSH and luteinizing hormone in the serum, while estradiol was increased. This in turn led to reduced anxiety, and improved menstruation and perimenopausal symptoms. The possible mechanism has been related to genes and proteins associated with the PI3K (phosphoinositide 3-kinase)/Akt/mTOR signaling pathway [64–66]. Han’s acu-point nerve stimulator treatment could improve the clinical pregnancy rate in patients with a decreased ovarian reserve during in vitro fertilization and embryo transfer cycles by increasing the antral follicle count and anti-Müllerian hormone levels and decreasing the estradiol level, FSH, and FSH/luteinizing hormone ratio [67]. Polycystic ovary syndrome remains one of the most common causes of anovulation in women of reproductive age, while nerve growth factor has been associated with its pathogenesis. Electro-acupuncture treatment has been shown to partly reverse the nerve growth factor abundance, specifically in the ovaries [68,69]. Acupuncture can suppress abnormal increase of body weight and decrease of plasma estrogen and estrin levels in a rat model of ovariectomy-induced osteoporosis [70,71]. In human studies, therapeutic effect of warm needle moxibustion on osteoporosis has been shown to be better than that of oral caltrate with vitamin D2 administration with a corresponding increase in estradiol levels [72]. Acupuncture has also been shown to reduce climacteric syndrome, associated with an increase in body weight, by decreasing the estrogen level [73,74]. Evidence shows that acupuncture is responsible for an increase in ovarian granular cell layer P450 aromatase. P450 aromatase is an enzyme that has a role in estrogen synthesis and improved endometrial receptivity at the time of implantation [74,75]. Electroacupuncture of “Sanyinjiao” (SP6) and “Guanyuan” (CV4) may upregulate uterine and ovarian estrogens in rats by affecting the hypothalamus—pituitary—ovarian axis [76–78]. Thus, acupuncture may have a significant therapeutic impact on estrogen- and ER-associated diseases, which is required to be explored further.

5. Conclusion

Here, we review the effect of different natural estrogenic modulators as well as acupuncture against these pathological conditions. Acupuncture shows little adverse effects. Some of the discussed natural compounds are approved by the United States Food and Drug Administration as therapeutic agents for other diseases and thus may be readily used, while others, after appropriate toxicological screening, may eventually develop into new therapeutics for estrogen-dependent diseases.