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In cellular biology, a receptor is a protein molecule usually found embedded within the plasma membrane surface of a cell. Its job is to receive chemical molecules (also called ligands) that can include peptides, neurotransmitters, and hormones. Once coupled like a key fitting into a lock, a specific series of tissue responses are initiated and affected intracellularly. For example, the acetylcholine receptor recognizes and responds to its ligand, acetylcholine. There are literally thousands of receptors in the body, including those specific to hormones like insulin, and for substrates like low-density lipoproteins (LDL). As a result of this many illnesses and disorders can be considered receptor related disorders, as this important relationship can be the key to learning more about these conditions and how to resolve them.
Optimum body function requires a perfect balance between the ligand such as hormone, its corresponding receptor, and associated feedback loops working in unison. Any malfunction or imbalance spells trouble.
There is a bioactivation and signalling journey that converts information of our surroundings outside the body into cellular chemial reactions within. This biochemical journey originates in the brain which converts senses received by smell, sight, or noise into chemicals called hormones that travel through the blood stream to target receptors. Once at the doorstop of the target organ the target receptor function acts as a gatekeeper and dictates how hormones outside the cells are converted into biochemcial signals inside the cell for a call to action. Receptor function is the final gateway for completing the signalling process from our senses to electrical energy. While some receptors will accept multiple ligands, active specific outcomes are usually limited to the exact matching ligand. In other words, while multiple ligands may couple and lodge with the receptor, action will only be initiated with one ligand receptor.
Many receptors have been identified, including those specifically for acetylcholine, epinephrine, norepinephrine, dopamine, and serotonin. They come in a full range of selectivity and sensitivity. There are at least four general groups of receptors:
Expression is a term we use to describe the ultimate effector responses after receptors are coupled with their respective ligands. Ligands can be called agonists when they induce the desired post-receptor events. They can also be called antagonists when the desired signaling is blocked. Modern medicine takes advantage of both of these characteristics in development of drugs. For example, aldosterone receptor antagonists are drugs designed to block aldosterone activation. By doing so, sodium retention within the cell is prevented, and fluid leaves the body as a result. It is widely used as a diuretic for heart failure.
There is a wide range of receptor expressions or possible responses. Expressions are modulated and fine tuned by the hormonal feedback and regulatory loops associated with each receptor. The intrinsic characteristics of the receptors themselves can also change with time depending on how they are used. For example, chronic stimulation of receptors can often result in reduced numbers of receptors as the body either down regulates or activates the associated negative feedback loops. A body overloaded with estrogen will generally have less estrogen receptors as a result because the body feels more is not necessary.
Take the case of postmenopausal women with low estrogen complaining of hot flashes. Many are prescribed estrogen for this, but symptoms continue. Progesterone is often then prescribed in addition to oppose and reduce estrogen load. Instead of getting better, symptoms of estrogen excess get worse. This can be explained. While on estrogen, receptor sites down regulate. Progesterone causes a re-activation of the estrogen receptors and a trigger-exaggerated response. More hot flashes are experienced instead of less. Astute and experienced clinicians can see this correlation and solve the problem by reducing estrogen as progesterone is added.
Lastly, depending on where the receptor sites are located, the desired function and expression changes. Consider the following:
As you can see, the body has many built in ways for receptors to be regulated thus determining their ultimate expression potential. It is a complex science.
For the body to work right and for you to feel good, receptor concentration and function needs to be maintained at optimal levels. This process is automatic and goes on in the body without us knowing the receptor sensitivity compared to their efficiency. How the receptor site responds to its chemical influence is determined by many factors. It is known that many receptors are adaptive structures as well as responsive to long-term changes in the receptor environment. Receptors can also adjust to change in specific ligand supply by regulation of their responsiveness to stimuli. Some people are highly sensitive to all kinds of medications with amplified responses compared to others. A small dose of over-the-counter sedating antihistamine medication, for example, may make them sleep for many hours. Others may need more medication than usual just to have the normal clinical effect.
Receptor sensitivity variability is at the center of such behavior. Cellular responses are generally dose dependent if all else is equal. However, some variations exist and that is why not everyone reacts to medications or supplements the same way. Receptor upregulation can lead to hyperfunction (or a hypersensitive state) that results in target organ overstimulation producing clinical syndromes of hormone excess. For example, estrogen receptor hyperfunction can trigger a state of estrogen dominance, leading to PMS, menstrual irregularity, endometriosis, fibroids, and even cancer. On the other hand, receptor hypofunction (or in a hyposensitive state) due to down-regulation may present with clinical features of hormone deficiency.
Furthermore, some receptors can directly influence and have a dramatic effect on the response of other receptors and affect their sensitivity. This is a process called heterologous desensitization. It explains why some people first taking progesterone alone can have estrogenic effects when they have not been on hormone replacement or estrogen before.
Some laboratory tests for receptor activity and receptor related disorders are available. They include studies for soluble transferrin, T-cell, interleukin-2, and HER2 receptor. Perhaps the most common receptor site measurement encountered in clinical medicine concerns the hormones estrogen and progesterone in a breast cancer setting. Typically the pathology report has a discussion on whether the tumor is estrogen positive (ER+) or not. An ER+ tumor is estrogen receptor positive, meaning that estrogen can attach itself to the receptors and enhance tumor growth. This is important because breast cancer is largely a hormonally driven cancer. Knowing that the receptor is sensitive to estrogen means that medicines that block estrogen binding such as tamoxifen can be deployed. Medicines such as aromatase inhibitors that reduce estrogen can be deployed as to reduce estrogen-related breast cancer.
Likewise, progesterone also can affect some breast cancer tumors by stimulating their growth. A PR+ tumor is progesterone receptor positive and because the progesterone receptor gene is regulated by the estrogen in normal reproductive tissues, and in MCF-7 human breast cancer cells, a tumor that is PR+ usually responds to estrogen.
Unfortunately, receptor site studies are still years away from being commercially viable on a large scale with the exception of estrogen and progesterone. Most receptor site studies occur in research facilities.
Here are a few examples of receptor related disorders and the illness associated with them that we know.
When someone experiences a stressful event, the level of cortisol in his or her blood rises. Activation of this cascade starts specifically with receptors in the hippocampus, where stress signals are received and the hypothalamus activated. Once activated, the hypothalamus secretes corticotropin-releasing hormone (CRH) that in turn triggers the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH released into the bloodstream travels to the adrenal glands, causing the production and release of cortisol, the body’s main anti-stress hormone. The body’s anti-stress response highway described above is called the hypothalamic-pituitary-adrenal axis (HPA).
Adrenal Fatigue Syndrome is a stress-induced neuro-endocrine dysfunction involving the dysregulation of the HPA axis and associated hormones. Hormones playing a key role in AFS genesis and progression include upstream chemical molecules such as CRH, dopamine, epinephrine, norepinephrine TSH, and ACTH. Important players of the downstream hormones at target endocrine glands include thyroid hormone, aldosterone, pregnenolone, DHEA, estrogen, progesterone, testosterone, cortisol and its various pro-hormones. Associated with each hormone are the target receptor sites, the effector response, and feedback loops.
As mentioned earlier, optimum hormonal homeostasis within the body depends on three main factors working in unison—hormone, receptor sites, and feedback loops. We will look at feedback loop issues now, and later, the main hormone of concern under the AFS setting.
There are two basic configurations of negative-feedback loops within the endocrine system:
This mechanism controls blood sugar, blood calcium, blood osmolarity and volume, blood K, and Na, among others. Response-driven feedback mechanisms act like a thermostat at home. You set the desired temperature as default. As the temperature rises to the preset threshold, change is detected and the air conditioning unit is turned on once the threshold is crossed. Room temperature lowers and the air conditioning unit turns off once the desired thermostat setting is reached. The same happens in our body, whether it is with cortisol, calcium, or a host of other hormones. Our stress hormones are kept at perfect levels throughout the day as a result, not too much and not too little. The body is made stable as a result, and this is the predominant mode of feedback loops among endocrine glands.
Much of the endocrine system is organized into endocrine axes, with each axis consisting of the hypothalamus and the pituitary and peripheral endocrine glands. AFS is a condition when there is dysregulation of the hypothalamic-pituitary-adrenal axis (HPA). This type of feedback loop involves a three-tiered configuration. The first tier is highest up on the command chain. It is represented by hypothalamic neuroendocrine neurons that secrete releasing hormones like CRH. Releasing hormones stimulate generally increasing the production and secretion of tropic hormones from the pituitary gland. This is the second tier. Examples include thyroid stimulating hormone (TSH) and adrenal cortical stimulating hormone (ACTH). Tropic hormones stimulate the production and secretion of hormones from targeted peripheral endocrine glands such as the adrenal glands (third tier). The peripherally produced hormones, namely cortisol, progesterone, DHEA, testosterone, and sex steroids typically have multiple effects on a variety of cell types. The main primary feedback loop involves feedback inhibition of pituitary tropic hormones and hypothalamic releasing hormones by the peripherally produced hormone. For example, with the HPA axis, excess cortisol activates the brain's glucocorticoid receptors and suppresses the production of CRH. It is through these feedback loops that the body maintains a tight lid to prevent excessive production and release of hormones once the body has enough. Malfunction of the negative feedback loops can lead to uncontrolled release of hormones that can be detrimental. Overall, negative feedback loops take care of our day-to-day function.
When it comes to survival, there are certain hormones that the body has designated to be used in emergencies only, like epinephrine and norepinephrine. Both fall into a class of chemicals called catecholamine. A negative feedback loop would be counterproductive during emergency situations. That makes perfect sense. In an emergency, you want as much epinephrine as possible if survival is perceived to be at stake. The body needs a system that encourages more production when it recognizes the need. Having a positive feedback system encourages this.
Lets take a look at epinephrine biochemically. Under physical or emotional stress, our body activates the fight-or-flight response, resulting in epinephrine release. It also leads to norepinephrine release from sympathetic nerve endings. The combined effect of catecholamines put our brain on full alert; increases heart rate and force of contraction, along with skeletal muscle changes that favor blood flow. Overall blood volume and circulation increases in the body. It should come as no surprise that those who are under stress have intermittent surges of epinephrine that could initiate or promote high blood pressure for those epinephrine sensitive people that are predisposed to high blood pressure.
When epinephrine is released under stress, as in the case of a fight-or-flight response, the body’s feedback instruction is to make even more. There is no shut off valve, or negative feedback, so to speak. Instead, a positive cascade ensues. More is released. This is the body’s way of making sure we have more than enough epinephrine in times of danger. This, however, comes at a price. If stress is unrelenting and the positive feedback loop is constantly working, the body’s epinephrine level goes higher and higher until the body is flooded in a sea of epinephrine. The person feels jittery and anxious. Heart rate goes up. Adrenaline rushes are experienced. These can be very harmful if left unchecked.
Positive loops are inherently unstable as a feedback mechanism because one is stretching the system to put out more and more hormone without rest once activated. Over time, such instability, if not controlled, will destabilize the body. Positive feedback loops are therefore not designed for everyday homeostasis but only for use in emergencies.
Catecholamines are a class of compounds including dopamine, norepinephrine and epinephrine. They are an integral part of our autonomic nervous system (ANS). The perfect balance between norepinephrine and epinephrine within the body allows us to function normally and yet have the ability to handle emergencies respectively.
Norepinephrine is the biological mother of epinephrine. It is a weaker hormone compared to epinephrine. Norepinephrine performs its actions on the target cell by binding to and activating adrenergic receptors. The target cell expression of different types of receptors determines the ultimate cellular effect, and thus norepinephrine has different actions on different cell types. It acts as a neurotransmitter in the brain, keeping us mentally sharp and alert. Outside the brain, it acts as a hormone peripherally and is largely responsible for the day-to-day control of vascular tone and heart function. Without norepinephrine, one cannot stand upright for long. Excessive norepinephrine, however, is not healthy either. One feels anxious, jittery and irritable, with heart pounding and impending doom sensations in a state known as sympathetic overtone.
Epinephrine elevation is normal during periods of stress as the body prepares for fight-or-flight. If its release is allowed to be chronically high, its negative affects start to surface also. Since epinephrine is more potent than norepinephrine, the body is put on edge to the extreme. Adrenaline rushes are common, and the inability to relax at night is the norm. Feeling wired and tired with severe insomnia is a nightly occurrence. Collectively, this state of a body flooded in norepinephrine and epinephrine is called reactive sympathetic response (RSR). This is an undesirable and unstable state because RSR triggers a positive feedback loop and amplifies the instability.
If left unchecked over time, RSR can trigger cardiac arrhythmias such as atrial fibrillation, postural hypotension, postural tachycardia and POTS-like symptoms. Multiple visits to emergency rooms are the norm with complaints of chest pain, cardiac arrhythmia, severe anxiety, shortness of breath, and a sense of impending doom. These are the workings of excessive epinephrine.
There are many adrenergic receptors in the human body. They are a class of G protein-coupled receptors sensitive to the catecholamines norepinephrine and epinephrine. They are activated by the sympathetic nervous system (SNS) and function to assist the body in dealing with crises requiring heightened levels of somatic activity. Within the central nervous system, norepinephrine serves as the primary neurotransmitter. In the peripheral nervous system, the work is shared by acetylcholine, norepinephrine, and epinephrine.
Peripherally, epinephrine not only acts as a hormone targeted at the heart to increase cardiac output, it also stimulates prejunctional adrenergic receptors. This facilitates the release of norepinephrine from sympathetic nerve endings. Norepinephrine, once released, is then converted into a co-transmitter by neuronal uptake and released to augment the simultaneous discharge of more norepinephrine. In other words, epinephrine potentiates more norepinephrine release. The body receives both epinephrine and norepinephrine effects. That is why epinephrine is called the emergency hormone.
When a body is in a state of RSR, the adrenergic receptors are constantly working on overdrive. If stressors are not removed and receptors are allowed to rest and regroup, breakdown of receptors can result, leading to a host of receptor-related disorders such as increased hypersensitivity of the receptor sites, amplification of normal receptor responses and a lowered receptor sensitivity threshold. These receptor related disorders, in turn, trigger a set of downstream problems, like a domino effect. Warnings of such receptor related disorders include onset or presence of paradoxical reactions, retarded recovery, frequent adrenal crashes, slow liver clearance, extracellular matrix congestion, delayed food sensitivities, bloating, skin rashes, and many others.
Let us now look at how key hormones of Adrenal Fatigue Syndrome interacts with their receptors.
When the HPA axis is activated under stress, the adrenal gland goes into overdrive to produce more cortisol. Cortisol, our main anti-stress hormone, prepares the body for a fight-or-flight response by flooding it with glucose. These supply an immediate energy to large skeletal muscles. At the same time, cortisol inhibits insulin production and prevents glucose storage, readying its immediate use. As well, cortisol potentiates the effect of epinephrine to increase heart rate, both of which force more blood to pump faster.
Cortisol, like epinephrine, is a short-term emergency hormone. Excessive cortisol output because of chronic stress leads to a state of cortisol excess in early stages of AFS as the HPA axis responds positively. As AFS progresses, cortisol output drops after reaching peak levels. The HPA axis eventually becomes overworked and exhausted. Those with advanced AFS usually have low cortisol throughout the day as a result. If stressors are not removed, overall cortisol output will reduce as AFS advances. The saliva 24-hour cortisol curve in advanced AFS is typically flat throughout the day instead of being high in the morning and low at night.
A low cortisol level means that the body will not be able to handle stress well. As a compensatory response, the body increases output of more epinephrine as last resort. The state of RSR is created, as the body is flooded with epinephrine. Cortisol is therefore a key anti-stress hormone that needs to be in perfect balance with epinephrine to avoid development of Adrenal Fatigue Syndrome.
Inherited mutations of the cortisol (a glucocorticoid hormone) receptor can occur. When this happens, the HPA axis is put on overdrive in order to increase ACTH and cortisol production. Plasma levels of cortisol is high but only minimal clinical symptoms of Cushing’s’ Syndrome is present. The concurrent increase in aldosterone from ACTH stimulation causes sodium retention and thus volume expansion. Hypertension results.
AFS is a common and often neglected cause of secondary hypothyroidism. Low thyroid function can be detected in the blood by a laboratory test called Thyroid Stimulating Hormone (TSH). This is a hormone released from the pituitary gland. It travels to the thyroid gland with the purpose of activating the thyroid glands to produce more thyroid hormone. The TSH level can be measured. A high TSH level indicates increase in thyroid hormone production due to insufficient thyroid hormone in the body or a state of hypothyroidism. A low TSH indicates the reverse.
The hallmark of AFS is fatigue of unknown origin. It is often misdiagnosed as primary hypothyroidism and treated with thyroid medications. Unfortunately, many do not get better. In fact, over 50 percent of hypothyroid patients on medication continue to complain of fatigue.
A host of illnesses can arise if any number of problems or defects occurs with TSH binding. For example:
Most people in advance AFS have concurrent hormonal imbalance involving the Ovarian Adrenal Thyroid (OAT) hormonal axis. This imbalance is a hallmark symptom of Stage 3 adrenal fatigue in women. The key underlying root cause of the imbalance is estrogen dominance (ED), where there is an increase of estrogen compared to progesterone on a relative and not absolute basis. ED represents a continuum of conditions from mild to severe including PMS, menstrual irregularity, fibrocystic breast, endometriosis and breast cancer, the more estrogen in the body relative to progesterone, the higher the risk. Estrogen effects in the body can go up with exogenous intake (from birth control pills, xenoestrogenic compounds or food from animals injected with hormones), reduced clearance from the liver due to congestion, and increased estrogen receptor site sensitivities. The normal progesterone to estrogen ratio by a saliva test should be about 200 to 1. The lower the ratio, the more prominent the estrogen dominance.
In the case of advanced AFS, there is also an intrinsic bias towards estrogen dominance as upstream hormones like pregnenolone and progesterone within the adrenal glands is shunted to make more cortisol downstream, draining pregnenolone and progesterone levels. This phenomena is called the pregnenolone progesterone steal. Estrogen becomes dominant with less opposing progesterone. Excessive estrogen binds with thyroid binding globulin (TBG), making less thyroid hormone available to the cells. ED therefore as an indirect cause of secondary hypothyroidism can occur, upsetting the OAT axis balance.
Estrogen and progesterone are two hormones that have to be in perfect balance for the body to feel good. Both hormones bind to intracellular receptors that act primarily in the cell nucleus. The level of receptor expression depends not only on the number of receptors activated but also on special modulator proteins that can amplify the signaling called co-activator. Co-repressors do the reverse. The combination of the quantity of receptor sites activated along with their modulators leads to a full continuum of gene expression changes within a cell that is dynamic and decides the overall estrogenic response for that cell type or tissue. Some people are highly responsive, while others may be blunted. Those who are highly responsive to estrogen may see increased fluid retention, heavy menstrual bleeding, and severe PMS symptoms when given estrogen, for example. The same volume of estrogen may not elicit any response at all from another person that is estrogenically blunted.
The following are a few examples of the many disorders or unusual symptoms that can arise when estrogen and progesterone receptors are imbalanced:
Knowing how to use estrogen and progesterone properly requires a complete and thorough knowledge of its physiological role, dosage, body composition, body constitution, body history, dietary habits, receptor site health, delivery system characteristics, etc. Relying on laboratory tests alone as a clinical guide often ends in therapeutic failure as the patient goes thru a never-ending roller coaster ride of trials and errors.
Most of us don’t think about our receptor health. Few of us even understand what receptors do in our body. Due to the lack of laboratory measurement, much of what we know about receptor dysregulation in a setting of AFS comes from clinical experience.
Always start any medical investigation with a detailed history. In the case of suspected receptor dysfunction, this is the only option. If one digs deep enough, subtle signs of receptor disorder can usually be located if present. That is why it is critical to have a good history taken by an alert practitioner fully knowledgeable in AFS and receptor disorders.
We are first-hand observers of the most severe cases of AFS. They come to us after failing all traditional and alternative approaches. Many are incapacitated and unable to work. Most are frustrated because their recovery is retarded or efforts fail.
Here are some alerts for considering receptor health issues when present in a setting of AFS:
Remember that the above alerts are qualitative in nature and can be highly subjective. Do not get too preoccupied with every single detail of each symptom as to the degree and validity. Each alert points to possible receptor disorders within the bigger scheme of hormone regulation and AFS specifically. It’s the collective big picture that is most revealing.
Receptor disorders are often subtle and subclinical when suspected in the AFS setting. Consideration usually arises when there is persistent failure of recovery efforts with gentle and non-stimulatory natural compounds, after liver and extracellular matrix decongestion, and stressors identified and removed. When the body fails to improve with every correct step taken, one has to look at receptor site issues as a possible deep-rooted cause.
Assessment of receptor function is primarily based on clinical experience. It is not an exact science because one does not exist at this point with any accuracy other than a select few receptors. A good and detailed history can bring up signs of receptor dysfunction. The key in determining ultimately if receptor disorder is present in an AFS setting comes down to correlating the clinical symptoms with receptor pathophysiology and recovery strategy at every point in time as receptor characteristics and properties can change with time.
Receptor dysfunction can be detected if one is constantly observant for such phenomena. Without this watchful focus, it is easy to miss the alerts.
We do know that the body self regenerates. And that applies to receptor sites as well.
Since there are no natural compounds or medications that can specifically rebuild or replace receptor sites, we will have to leave this up to the body. Most of the time, this is possible from our clinical experience if we provide the body with the necessary raw nutrients for the body to carry out its work. Unfortunately, few are started on such a program because of the lack of attention to receptor health overall.
Most sufferers of AFS are weak and fragile by the time receptor derangements are suspected or surface. They simply do not have the resilience and rebound capacity if the body is stressed. Many are in catabolic state, frustrated, and feel hopeless. They are also impatient as a result, lacking faith in the medical community as a whole, whether it is allopathic or naturally oriented physicians. Most have been abandoned by their doctor and left to self-navigate. Managing expectations becomes very important.
Receptor recovery is but one component of a comprehensive adrenal recovery program. Concurrent attention has to be given to ensure that the body’s electrolytes are stable, sleep maximized, catabolic state reversed, aldosterone function supported, liver decongested, extracellular matrix optimized, paradoxical reaction minimized, bioavailability of nutrients maximized, and adrenal crashes avoided. There are many moving parts that can be overwhelming.
Some trial and error is inevitable in the best of hands, and periodic setbacks surface. Blind trial and error exercises without due comprehension of the complexities may subject the body to unpredictable outcomes that generally worsen the overall condition over time.
Generally speaking, receptor site recovery is a very slow process. Depending on the degree of damage and the body’s constitution, expect twelve months or more. Those who are younger and strong constitutionally tend to do better and in a shorter period of time, as well as those who have a comprehensive recovery plan in place that is realistic and closely monitored. Here are some tips:
For example, laboratory tests may show a low level of pregnenolone. If there is a pregnenolone steal phenomena in place, as commonly occurs in AFS, a low pregnenolone level is perfectly normal and does not represent pregnenolone deficiency or failure of its receptor site function. Forcing more pregnenolone into the body just because the laboratory number is low will be counterproductive and may trigger an adrenal crash. The same can be said for pregnenolone, DHEA and thyroid medicine. They should be prescribed only if needed after the root cause is known.
Receptors should be looked at as a master network of self-regulating keys that are omnipresent in every cell, acting as gatekeepers and modulators of cellular function. No discussion on hormone is complete without consideration of their receptor site functions. Whether the discussion is on thyroid, ovarian, or glucocorticoid hormone, knowing their corresponding receptor site function will go a long way to explain why most people embarking on these hormone replacements continue to complain of symptoms, and why without extensive clinical experience, their titration beyond what is recommended by the standard textbook is much harder than what meets the eye. Those with advanced AFS are particularly at risk due to their weakened state. Fortunately, there are subtle clinical signs that alert us to focus on receptor disorders and tools to facilitate the recovery. Given the body the necessary raw material for it to initiate a self-healing process. Do not force the body. Do regular and close follow up for maximal effect as the body will change during the recovery process.
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