A New Insight into Estrogen Signaling: Yin

Abstract

During recent years, new advances in the field of estrogen signaling (e.g., the discovery of the second estrogen receptor named ERβ) have led to the conclusion that all the major human tissues are estrogen-responsive. The impact of estrogen on human health is far more complex and stronger than scientists had previously thought. Several scientists suggested that the interplay between ERα and ERβ (antagonism, synergism, etc.) simulates a Yin–Yang relationship. This article is intended to integrate the Yin–Yang theory of Traditional Chinese Medicine with modern scientific findings on estrogen signaling to offer a better understanding of the complex interactions between ERα and ERβ. A different approach, such as that of Yin–Yang theory, may complete the standard scientific perspective, reveal hidden meanings of the tissue-dependent ERα–ERβ predominance, and reveal new aspects of estrogen-receptor imbalance.

Introduction

E strogens have steroid receptors that have profound effects not only on both the female and male reproductive systems, but also on almost all the organs. There are two types of estrogen receptors widely distributed in human body: (1) estrogen receptor–alpha (ER-α) and (2) estrogen receptor–beta (ER-β). For a long time, there was no knowledge of the presence of ERβ. The relatively recent discovery of the second ER in 1995¹ was a real revolution in understanding estrogen signaling. Moreover, ER-α and ER-β have markedly different tissue distributions and functions. All of these findings have raised a number of questions regarding the physiologic roles of these two receptors. It has also long been known that estrogens have either protective effects (e.g., cardioprotective, antiosteoporosis, immunomodulatory, etc) or pathogenic roles in a wide variety of diseases (e.g., uterine and breast cancer, endometriosis, metabolic diseases, etc.),^2

–5 thus showing an intrinsic duality.

During recent years, there has been an intense debate concerning this estrogenic duality and the complexity of the ER interrelations. Use of the standard modern scientific approaches, which “break down” the whole into the smaller and smaller parts, might lead to the loss of knowledge about many important biologic factors of significance. A different approach and a paradigm shift are required to understand all the aspects of estrogen signaling. Yin–Yang theory may complete the standard scientific perspective and reveal alternative, or even hidden, meanings of the “nature's way to accomplish the subtle regulatory changes of estrogen signaling as a response to ever-shifting physiologic requirements.”⁶ Some of these aspects are discussed in this article.

A literature search was conducted, using PubMed and Highwire, to collect data from studies on estrogen signaling. All the data collected were published in English and available up to August 2011. Search terms used were: estrogen receptors, estrogen receptor alpha, estrogen receptor beta, and estrogens. A supplemental manual search of references in the articles that were chosen and references from different classical Chinese medical or bioscientific textbooks was performed.

Yin–Yang Theory—Introductory Notes

Yin–Yang theory of classical Chinese medicine advocates that the universe is run by a single principle, the Tao, or Great Ultimate. This principle is divided into two opposite and complementary forces, Yin and Yang, which oppose one another in their actions, while also forming an inseparable union.^7,8 Yin and Yang are variously described as several pairs of complementary qualities (Table 1).

Table 1.

Yin–Yang Pairs of Qualities

Yin qualities/categories	Yang qualities/categories
Passive	Active
Female	Male
Son	Father
Coldness/Water	Heat/Fire
Lower part/Downward direction	Upper part/Upward direction
Interior/Inward direction	Exterior/Outward direction
Darkness	Brightness
Turbid	Clear
Stillness	Movement
Tranquility	Agitation
Retarded	Accelerated
Substance	Function
Night-time	Daytime
Storing	Destroying/Killing

Yin and Yang are descriptive terms representing qualities of nature. These terms are relative, describing characteristic tendencies of one thing with reference to another thing, and do not refer to any unique concrete or existing structure within modern scientific theory.

Pervasiveness

Yin and Yang permeate all the microcosms simultaneously within the one grand macrocosm, being in continuous reciprocal restriction and interaction. All phenomena are results of the interplay of these two opposite aspects. For example, each cell has membranes or nuclear receptors, which is a Yin aspect. Cellular functions are ruled by various hormones—comprising a Yang aspect—that bind to the receptors.

Changeability

The Yin or Yang of each phenomenon is not absolute or unchangeable, but, rather, can change as a response to ever-shifting natural conditions. In the previous example, this characteristic is expressed in the downregulation or upregulation of hormonal receptors (Yin) that are influenced by the fluctuations of hormonal concentrations (Yang). One aspect of this changeability is infinite divisibility. Each Yang or Yin factor can be subdivided further into a pair of Yin–Yang factors ad infinitum. For example, hormonal receptors belong to Yin, and hormones belong to Yang. However, both receptors and hormones can also be divided into Yin and Yang. Female sexual hormones are Yin; male sexual hormones are Yang. Among the female sexual hormones, estrogens are Yin, cooling and producing fluids (i.e., estrogens have a temperature-depressing effect and increase cervical-mucous secretion), while progesterone is Yang, transforming and drying fluids (i.e., progesterone has a thermogenic effect and transforms cervical-mucous secretion, which becomes thicker).^9,10 Therefore Yin–Yang principles have the attribute of relativity: any aspect characterized as having a specific quality (either Yang or Yin) may, nevertheless, be categorized according to another perspective and, in addition, be assigned a different quality.

The Four Basic Principles of Yin–Yang Theory

Mutual opposition and restraint

Yin and Yang are opposites but are still united. Yin attracts Yang, Yang attracts Yin, and the greater the difference is, the greater the attraction will be. Yin repels Yin, Yang repels Yang, and the greater the similarity is, the greater the repulsion will be. As has been said: “Opposition is the aspect of the contrary between the two; unity is the aspect of the complementarity between the two.”⁷ Everything has its relative opposite. All changes result from the opposition and reciprocal inhibition of Yin and Yang.⁸ For instance, the oxidative agents in the human body including free radicals are Yang (aggressive), while endogenous antioxidants are Yin (protective). The excess of free radicals (e.g., hydroxyl radical HO• or superoxide anion O₂ ⁻) in the body can lead to cumulative oxidative damage of lipids, proteins, and DNA. The body is able to prevent this state of oxidative stress by using a complex antioxidant-defense system composed of enzymatic and nonenzymatic agents, which counteract the damaging power of free radicals. An antioxidant can either “extinguish the fire” (e.g., superoxide dismutase [SOD]) or “sacrifice” itself (e.g., albumin, vitamin E) to protect a more-important molecule. The continuous fight between these two opposing forces results in the redox balance of the tissues.

Interdependence

One thing cannot exist without another opposite thing. Nothing is completely Yin or completely Yang; each contains the seed of its opposite. Without Yang there is no Yin; without Yin there is no Yang. They rely on each other for existence, coexisting in mutual dependence with one another in a single entity. Yin nourishes, sustains, and controls Yang and vice versa. “Yang is born of Yin, and Yin is born of Yang.”⁸ This relationship of mutual dependence could shed light on how synergistic phenomena appear in nature. Ligand-induced functional synergism based on receptor transactivation is an example of Yin–Yang interdependence. Binding of a coactivator molecule to a receptor (e.g., Yin type) can enhance the activation of another receptor (e.g., Yang type) belonging to the same class (“Yang is born of Yin and vice versa”).

Mutual reliance (or consumption-support)

This is a process of quantitative change. The lessening of Yin leads to an increase of Yang, and vice versa. Some concepts regarding this include⁸: “If Yang is overly powerful, then Yin may be too weak. If Yin is particularly strong, then Yang is apt to be defective.” “Yin waning as Yang waxes …” and “Yang waning as Yin waxes. …” This relationship of mutual reliance clarifies how sequentiality (rising and declining) and cycles appears in nature (e.g., the sequence of the seasons). According to Traditional Chinese Medicine (TCM), the menstrual phases follow the regular waxing and waning of Yin and Yang and result in variations in body temperature (a lower temperature occurs during the follicular phase and a higher occurs temperature during the luteal phase).

Mutual transformation

This is a process of qualitative change. Extreme Yang produces Yin. Extreme Yin produces Yang. “When extreme, Cold gives rise to Heat; and when extreme, Heat gives rise to Cold.”⁸ For instance, in the male body, testosterone (Yang) is reduced into dihydrotestosterone, which is extreme Yang, being more active than testosterone as an androgen. Dihydrotestosterone (extreme Yang) is than enzymatically reduced into the 3β-androstanediol, which is an estrogen (Yin).²

The autoregulation of Yin and Yang illustrated by the mutual consuming—increasing and transforming relationships—is the key to homeostasis in the body. Normal physiologic conditions require avoidance of extremes of Yin and Yang.

Expression Patterns

Yin–Yang tissue predominance

Differential tissue distribution of ERs is a hallmark of Yin–Yang tissue predominance.

Estrogens exert their actions via two types of nuclear receptors. The discovery of the ERβ led to the conclusion that estrogen signaling is far more complex than it was thought to be earlier.¹¹ For a long time, the presence of ER could not be confirmed definitively in certain human organs and tissues. There is now a consensus that there are differential distribution of ERs and the following types of organs, tissues or cells¹²:

(1) ERα-negative ERβ-positive organs/tissues/cells (e.g., neurons of cerebral cortex, thyrocytes)

(2) ERα-positive ERβ-negative organs/tissues/cells (e.g., hippocampus, Purkinje cells in the heart)

(3) ERα- positive ERβ-positive organs/tissues/cells (e.g., uterus, breast)

(4) ERα- negative ERβ- negative organs/tissues/cells (e.g., endocardium).

The two receptors have distinct, but overlapping expression patterns.¹³ The organs that express both ERs usually have a specific dominance, either ERα or ERβ. A literature analysis^2,13,14 on this topic has led to the conclusion that ERα tends to be the dominant receptor in Yin organs and ERβ tends to be the dominant receptor in Yang organs (Table 2).

Table 2.

Estrogen-Receptor Dominance in Yin–Yang Organs ^a

ERα-dominant organs (Yin organs in TCM)	ERβ-dominant organs (Yang organs in TCM)
Heart^13,b	Small Intestine¹⁴
Spleen²	Stomach¹⁴
Lungs¹⁴	Large Intestine¹⁴
Kidneys^13,c	Bladder^13,18,d
Liver¹³	Gallbladder (not yet clear the predominance, although both receptors are expressed); loss of ERβ expression at cancer front correlates with tumor progression^e suggests at least a functional “dominance” of ERβ in gallbladder.

Organs in TCM do not necessarily correspond with Western medical concepts of organs.

Couse JF, Lindzey J, Grandien K, et al. Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERα) and estrogen receptor-beta (ERβ) messenger ribonucleic acid in the wild-type– and ERalpha-knockout mouse. Endocrinology 1997;138:4613–4621.

Jelinsky SA, Harris HA, Brown EL, et al. Global transcription profiling of estrogen activity: Estrogen receptor alpha regulates gene expression in the kidney. Endocrinology 2003;144:701–710.

Kuiper GGJM, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997;138:863–870.

Sumi K, Matsuyama S, Kitajima Y, Miyazaki K. Loss of estrogen receptor beta expression at cancer front correlates with tumor progression and poor prognosis of gallbladder cancer. Oncol Rep 2004;12:979–984.

ER, estrogen receptor; TCM, Traditional Chinese Medicine.

The receptor dominance could be higher (e.g., liver),¹³ even absolute (e.g., hepatocytes expressed only by ERα),¹² or lower (e.g., lungs)¹⁴; this dominance is probably dependent on the relative ratio of Yin–Yang of the particular organ. There are some contradictory results concerning the lungs, with some researchers reporting an ERβ dominance.¹³ However, another study showed a very low dominance of ERα in the human lungs (the amount of ERα mRNA was approximately equal to ERβ mRNA but was still slightly higher),¹⁴ which confirms the current authors' view on ER distribution as a hallmark of Yin–Yang predominance. These almost-equal proportions could be correlated with the double susceptibility of the lungs to both Heat and Cold: “The Lung is the delicate Zang, neither heat nor cold is appropriate.”¹⁵

TCM recognizes five Yin organs and five Yang organs, also known as “Zang” (“depot”) and “Fu” (“palace” or “cavity”) organs respectively (Table 2). The function of the Yin organs is to produce and store fundamental substances such as Blood, body Fluids, and Essence. The Yang organs are responsible for digestion and excretion. Usually, Yang organs are cavitary organs, and Yin organs are noncavitary organs.

Concerning the Pericardium and Triple Heater, we have found there are not enough research studies to draw a conclusion regarding their ER predominance. More experimental results are needed to allow an integration between TCM and biomedicine on this topic. Furthermore, it is very difficult to approach the Triple Heater concept from a bioscientific point of view, because this concept is not recognized by biomedicine. New laboratory tools should be developed to promote understanding of Triple Heater complexity from a bioscientific perspective.

Active and passive principles

ERα represents the “active” or Yang principle, whereas ERβ represents the “passive” or Yin principle.

ERs, like all steroid-hormone receptors, are transcription factors that alter gene expression. Estrogen-ER binds to certain specific control regions in DNA, called estrogen-responsive elements (EREs), and regulates transcription.¹⁶ The major physiologic estrogen, 17β-estradiol (E2), has a similar affinity for both ERs but has a differential action. When estrogen binds to ER-α, this activates transcription of certain genes, and on the contrary, when estrogen is complexed with ERβ, this appears to turn off gene transcription.

Estradiol E2 in the presence of ERα produces certain effects (e.g., proliferative, antidifferentiative effects), but, in the presence of ERβ, the same hormone has exactly the opposite effects (e.g., antiproliferative, prodifferentiative effects).¹⁷ Therefore, several scientists,^18,19 suggested a complex Yin–Yang relationship between the two types of estrogen receptors. It seems that ERα represents the “proactive” or Yang principle, whereas ERβ represents the “counteracting” or Yin principle.

The intrinsic complexity of ER interrelations reflects the Yin–Yang dynamic in the following ways:

(1) When ERs are coexpressed, ER-β (Yin type ER) inhibits ERα-mediated gene transcription in the presence of ERα (Yang type ER). This finding reflects the Principle of Interdependence: Yin and Yang are reciprocally regulated and inhibited by each other in such a way that a continuous dynamic balance is maintained.

(2) In the absence of ER-α, ERβ (an extreme Yin situation) can partially replace ER-α (Yang type-ER).¹⁹ This finding reflects the Principle of Mutual Transformation: Extreme Yin produces Yang.

Discussion

The current authors posit that ERβ appears to act as a dominant regulator of estrogen signaling.¹³ From a classical perspective, it could be said that ERβ is the “minister,” while the ERα is the “ruler.” In the absence of the ruler, the minister can partially replace the ruler (“The ruler is Yang, the minister is Yin”²⁰).

There are scientists who disagree with this Yin–Yang perspective on ERs. Rissman has suggested that the relationship between these two receptors is “beyond Yin–Yang,” limiting the Yin–Yang aspects only to the complementarity between ERα and ERβ.²¹ He has stated that the other two types of interactions between the two estrogen receptors, which are the synergistic and sequential ones, are not covered by Yin–Yang theory. His critique represents a partial understanding of Yin–Yang theory. The synergism of ERs (i.e., the combined effects of the two receptors on the production of the neuropeptide oxytocin and its receptor) may be correlated with the interdependence characteristic of Yin–Yang principles (see Principle of Mutual Reliance: “Yin nourishes and sustains Yang and vice versa”). The sequential relationship between ERα and ERβ (e.g., the separate actions of the two receptors in activation and organization of sexually dimorphic reproductive behaviors) may be a reflection of the Mutual Consuming-Increasing relationship of Yin–Yang principles.

Other arguments for this Yin–Yang predominance of ER are:

(1) Dominance of ERβ (Yin type ER) in both adult ovaries ²² and testis. ^23,24—In Chinese medicine, Yin Jing (Essence) moves from the Kidney to the ovaries/testes and becomes ovule/sperm, or in other words, “Yin supports action of Jing.”

(2) Distinct receptor behavior in specific circumstances—For instance, long-term exposure of primary endothelial cells to E2 increases the expression of ERα, but decreases that of ERβ.²⁵ E2 is a female hormone with a strong Yin trait, which is reflected in its biologic effects: promotion of follicle growth and ovule development (Yin supports the action of Jing/Essence) and stimulation of cervical glands to secrete mucus with nutrients (Yin creates fluids). E2-dependent increase of ERα reflects the Principle of Interdependence between Yin and Yang: “Yin is born of Yang.” At the same time, E2-dependent decrease of ERβ reflects the Principle of Mutual opposition and restraint: “Yin repels Yin.”

(3) ERα uterine dominance—ERα mRNA expression was more prominent than that of ERβ in uterus in all cell types throughout the menstrual cycle.³⁰ The fact that ERα is the dominant receptor in the adult uterus is highly suggestive for these bioscientific-classical correspondences. Uterus in TCM is considered to be the most important extraordinary Yang organ.

(4) ER mechanism of action—ERα contains an activating protein 1 (AF-1), which produces a high level of transcriptional activity (“Yang is active.” “That which is accelerated is Yang.” Su wen 7). ERβ, unlike ERα, contains an activating protein 1 (AF-1), which does not produce transcriptional activity, or moreover, might produce repressive activity (“Yin is passive.” “That which is retarded is Yin.” Su wen 7).^7,13,25

Other scientific results suggest the functional opposition between ERα and ERβ: ERα is proliferative, while ERβ is antiproliferative; ERα promotes glucose uptake by cell, while ERβ inhibits this process, etc. These aspects are analyzed from Yin–Yang perspective (Table 3).^{26

–36}

Table 3.

Functional Opposition Between ERα and ERβ Reflecting Yin–Yang Opposition

ERα (Yang principle)	ERβ (Yin principle)	References
Dominant in mature uterus, which is ready for pregnancy (“Yang gives life” Su wen 5)	Dominant in immature uterus, during development (”Yin stimulates growth” Su wen 5)	^7,27
Potent proliferative effects in the uterus and breast—creates predisposition to cancer (“Yang kills” Su wen 5, or Yang is aggressive, destroys the structure)	Antiproliferative & prodifferentiative effects in the uterus & breast—prevents cancer (“Yin stores” Su wen 5, or Yin is defensive, maintains the structure)	^2,7,28,29
—	Predominant in normal breast (“Yin creates fluids”) & bone marrow (Jing/Essence, which is Yin, produces bone marrow).	^2,30
Lack of elastic recoil (prevents synthesis of collagen; “In the case of rough movements, the Yang qi is present in surplus” Su wen 17)	Elastic recoil in uterus & lungs, etc. (prevents degradation of elastin & collagen by proteases; “In the case of smooth movements, the Yin qi is present in surplus” Su wen 17)	^7,31,32,33
Downregulates the cellular export of Na⁺ in efferent ductules (“the outside is Yang” or the outward direction, Su wen 4)	Downregulates the movement of Cl⁻ into the cell in efferent ductules (“the inside is Yin” or the inward direction, Su wen 4)	^7,34
Prevents increase in body fat content	Adipogenic phenotype; increases body fat content	^7,36
Antidiabetogenic	Diabetogenic
Stimulate expression of GLUT4 in muscles and glucose uptake	Inhibits expression of GLUT4 in muscles
Yang transforms qi” Su wen 5)	(“Yin completes physical appearance” Su wen 5)

ER, estrogen receptor.

The five Zang (Yin organs) have Yang receptors, while Fu (Yang organs) have Yin receptors.

Each organ has a Yin and a Yang aspect, even if five organs are overall considered to be Yin, and five organs are considered to be Yang. Part of Yin is in Yang and part of Yang is in Yin (see Principle of Interdependence). Yin contains a seed of Yang, and Yang contains a seed of Yin, or, in other words, nothing can be totally Yin or totally Yang in nature. For example, a saying of Chinese medicine emphasizes that “the body of the Liver is Yin while its function is Yang.”¹⁵ ERs mediate together with other receptors the organ functions, therefore it is natural for a Yin organ (e.g., the Liver) to express a Yang receptor (ERα) dominantly and, vice versa, for a Yang organ (large intestine) to express a Yin receptor (ERβ) dominantly.

Conclusions

Both TCM and bioscience agree that balancing opposites is essential to health, and unbalancing opposites characterizes disease. The ancient Yin–Yang balance model is similar to the ERα–ERβ balance model.

The potential sites of estrogen action have been extended after the discovery of ERβ to the entire body system. Thus, pervasiveness of Yin–Yang is reflected in the widespread distribution of ERs in the body.

Although more information on the impact of estrogen signaling on human health has been revealed, several questions still remain to be addressed in this evolving field. For example, can ERα/ERβ tissue predominance be used to tell if a person's Yin and Yang is balanced/imbalanced? Do patients who are weak in Yin according to TCM have decreased ERβ expression and vice versa? Do plants that are Yin tonics induce a higher expression of ERα in Yin organs and do Yang tonics induce a higher expression of ERβ in Yang organs? Furthermore, can we extend these correlations with Yin–Yang theory to other hormones and assemble more endocrine assays into a package to diagnose and monitor accurately Yin–Yang syndromes using laboratory tools? This integrative approach has also potential applications in the field of probabilistic models. Yin–Yang theory might become a prediction-estimation tool. For instance, because ERα is a Yang-type receptor, which is highly expressed in Yin organs, the current authors posit that it can be predicted that ERα might be the predominant receptor in the adult human pericardium and all the structures ruled by the energetic organ that is called Pericardium in TCM (a Yin-type organ).

These reflections on estrogen signaling and Yin–Yang theory illustrate how an integrative approach based on both classical and bioscientific medicine can lead to unexpected discoveries that may signify an important paradigm shift away from the conventional reductionist model toward a holistic model. The reductionist model, which is based on a fragmented approach, hampers understanding of the complex molecular networks within the human body. The defects of this reductionist model could be avoided by using a holistic theory-based approach, such as that of TCM. This article has shed some light on how classical Chinese concepts could help promote understanding of biomolecular complexity. More answers are waiting to be revealed.

Footnotes

Acknowledgments

This study has been supported by Contract No. 42163/01.10.2008, from the Programme “Partnerships in Priority Fields,” in the Ministry of Education, Research and Youth, in Romania.

Disclosure Statement

No competing financial interests exist.

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A New Insight into Estrogen Signaling: Yin–Yang Perspective

Abstract

Introduction

Yin–Yang Theory—Introductory Notes

Pervasiveness

Changeability

The Four Basic Principles of Yin–Yang Theory

Mutual opposition and restraint

Interdependence

Mutual reliance (or consumption-support)

Mutual transformation

Expression Patterns

Yin–Yang tissue predominance

Active and passive principles

Discussion

Conclusions

Footnotes

Acknowledgments

Disclosure Statement

References