Receptor Disorders and Adrenal Fatigue Syndrome – Full Version

By: Michael Lam, MD, MPH; Justin Lam, ABAAHP, FMNM; Dorine Lam, RDN, MS, MPH

Your brain can be affected by Adrenal FatigueIn 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).

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.

Biochemical Activation

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, 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.

Types of Receptors

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:

  • Receptors as enzymes: These receptors usually span the cell membrane. Once bound to the ligand, there is an increase in the phosphorylation of intracellular proteins. Phosphorylation is a chemical process in which a phosphate group is added to an organic molecule. In living cells phosphorylation is associated with respiration that takes place in the cell’s mitochondria resulting in ATP formation.
  • Receptors that use the G protein as their transducer: Once coupled a variety of pathways are activated, including adenylyl cyclases and phospholipases. Phospholipase C (PLC) activation by cell surface receptors has been recognized as a fundamental early transmembrane signaling event that triggers a wide variety of cellular responses. These range from egg fertilization through immune cell activation to hormone secretion.
  • Receptors that activate transmembrane ion channels to allow entry of molecules from the extracellular to intracellular space. These channels are also called ligand-gated ion channels, which open to allow sodium, potassium, calcium and chloride ions to pass through the membranes into the cells.
  • Receptors located intracellularly that increase or decrease DNA transcription, either by binding DNA or by modulating the effects of histones. Steroidal hormones like estrogen and progesterone are good examples.

Receptor Expression

Receptor molecules that could be affected by Adrenal FatigueExpression 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 often can 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:

  • Histamine H1 receptors are located in the endothelial cells and smooth muscles, affecting vascular and skin integrity.
  • Histamine H2 receptors are located in the GI track and control acid secretion, abdominal pain, and heart rate.
  • Histamine H3 receptors are located in the central nervous system, modulating sleep and appetite.
  • Histamine H4 receptors are located in the thymus, white blood cells, colon, and spleen.
  • 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.

    Receptor Sensitivity

    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, responsive to long-term changes in the receptor environment. As well, receptors can 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 anti-histamine 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. Receptors up regulation can lead to hyperfunction (or a hypersensitive state) that results in target organ overstimulation producing clinical syndromes of hormone excess. For example, estrogen receptor hyper function can trigger a state of estrogen dominance, leading to PMS, menstrual irregularity, endometriosis, fibroids, and even cancer. On the other hand, receptor hypo function (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.

    Laboratory Studies

    Some laboratory tests for receptor activity 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. Clinically 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 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. 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.

    Receptor Site Disorders

    Here are a few examples of receptor site disorders and the illness associated with them that we know.

    • Parkinson’s disease (PD) is a common progressive neurodegenerative disorder. Pathologically, this disease is characterized by the selective dopaminergic neuronal degeneration in the substantia nigra. The use of levodopa (L-dopa) successfully reduces motor symptoms.
    • Central Sensitivity Syndrome (CSS) is a group of syndromes bound by the common mechanism of central sensitization (CS) involving abnormal hyper excitement of the central neurons. Examples include fibromyalgia syndrome, chronic fatigue syndrome, irritable bowl syndrome, restless leg syndrome, myofascial pain syndrome, multiple chemical sensitivities, and posttraumatic stress disorder. Adrenal Fatigue Syndrome (AFS) may fall into this category.
    • Defects in G protein activity can lead to parathyroid hormone resistance. This can occur as an inherited or idiopathic form called pseudohypoparathyroidism (PHP).
    • Vitamin D receptors (VdR) are widely distributed in several normal human tissues like the intestine, kidney, liver, prostate, bone, thyroid, skin, adrenal, and muscle. Defects can lead to dysregulation of calcium and phosphate homeostasis.
    • Low serotonin receptor levels are linked to depression. Today’s antidepressant drugs called selective serotonin reuptake inhibitors (SSRIs) work by increasing serotonin levels in the brain. Examples are Prozac (fluoxetine) and Zoloft (sertraline). There are known close linkages between the serotonergic system and the norepinephrinergic system within the central nervous system. Norepinephrine, the neurotransmitter affected by some antidepressants, is also involved in depression modulation.
    • Familial hypocalcaemia and hypercalcaemia are autosomal dominant disorders caused by a mutation of the calcium receptor. The calcium receptor is the key to enable endocrine control of ionic calcium in the extracellular matrix. Receptor disorders can lead to disorders of calcium homoeostasis.
    • Insulin receptor gene mutation can lead to defective insulin receptors and a reduced ability for insulin to be coupled. In obesity, type 2 diabetes, and other states of insulin resistance, high levels of extracellular insulin may be found and is associated with deregulated insulin receptors at the cell surface. Metabolic imbalances can ensue.

    Stress, HPA Axis and Adrenal Fatigue Syndrome

    The adrenal glands are key structures in the process of Adrenal FatigueWhen 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.

    Negative Feedback Loop

    There are two basic configurations of negative-feedback loops within the endocrine system:

    Response-driven feedback loop. 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.

    Endocrine axis–driven feedback loop. 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.

    Positive Feedback Loop

    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—Friend or Foe

    Catelcolamine is 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.

    Adrenergic Receptors

    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 cotransmitter 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.

    Estrogen and Progesterone Receptor Disorders

    When a body is in a state of RSR, the adrenergic receptors are constantly working on overdrive. If stressors are not removed and receptors allowed to rest and regroup, breakdown of receptors can result, leading to a host of receptor disorders such as increased hypersensitivity of the receptor sites, amplification of normal receptor responses and a lowered receptor sensitivity threshold. This in turn triggers a set of downstream problems, like a domino effect. Warnings of such trigger events 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 AFS interacts with their receptors.

    Cortisol Receptors Disorders

    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.

    Thyroid Receptor Disorders

    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:

    • The TSH receptor binds to cell surface receptors that are structurally similar to adrenergic receptors. Hyper stimulation or hypo stimulation of adrenergic receptor function can lead to symptoms of secondary hyperthyroidism or hypothyroidism respectively. TSH can be normal and is not a good indication of underlying thyroid function.
    • Thyroid receptors are linked to the G proteins for subsequent intracellular signal transduction. Genetic disruptions and dysregulation of the G protein system can result in cAMP production being turned on continually, resulting in signs and symptoms of McCune Albright syndrome that include hyperthyroidism in 50 percent of the cases.
    • Anti-bodies can damage thyroid receptor sites. Anti TPO antibodies directed against the thyroid peroxidase, Anti TgAb directed against thyroglobulin, and TSH receptor antibodies (TRAb) have been discovered. The TRAbs may again be divided into the thyroid stimulating antibodies (TSAb), which activate the TSH receptor or those, which inhibit the TSH receptor (TBIAb), leading to a full spectrum of thyroid disorders.
    • Grave’s disease is thyroid disorder characterized by the presence of TSAbs, which bind to TSH. Once activated, the TSH receptor mimics the actions of TSH. Clinical hyperthyroidism results accompanied by an enlarged gland. Several different clones of TSH receptor antibodies may co-exist. At any point in time, one of them may predominate. The predominant antibody can change over from stimulatory to inhibitory, affecting ultimate receptor expression.
    • TSH receptor (TSH-R) mutations: Mutations in the TSH-R gene can lead to a pseudo-activation of the TSH-R that in turn, leads to the ongoing stimulation of the G protein resulting in chronically high levels of intracellular pathways including cAMP. Here patients present clinically with symptoms of hyperthyroidism without evidence of autoimmune thyroid disease (i.e., Grave’s disease). TSH-R mutations have also been associated with hypothyroidism on the other extreme.

    OAT Axis Imbalance and Estrogen Dominance (ED)

    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 Receptor Disorders

    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:

    • Progesterone alone can lead to an amplified estrogen effect in a heterologous desensitization response mentioned earlier. This explains why a small number of people starting on progesterone therapy experience an estrogenic effect instead, with fluid retention, irritability, heavy menses, and PMS.
    • Estrogen and progesterone need each other to work best. Sometimes progesterone does not have the desired clinical effect without some estrogen being concurrently given. Estrogen leads directly to or primes the production of progesterone receptors (PRs) in its target tissues, such as the uterus, for subsequent progesterone biologic action. This is why bio-identical hormone replacement with both estrogen and progesterone works best.
    • For those already on long-term estrogen replacement, the addition of progesterone can amplify the estrogen effect. Chronic stimulation of ERs can reduce estrogen receptor numbers as the body either down regulates or activates the associated negative feedback loops mentioned earlier. A body overloaded with estrogen will generally have less estrogen receptors because the body feels more is not necessary. Progesterone reactivates the ERs and amplifies the estrogenic effect. Concurrently, progesterone also down-regulates uterine ERs and inhibits ER expression. The exact net response varies from person to person.
    • The amounts of estrogen receptors are most abundant in reproductive tissues such as the mammary glands, uterus, and vagina. ERs are present also in ovary, adipose tissue, and adrenal cortex. This has important clinical implications. Many are led to believe that a total hysterectomy with ovaries removed would permanently reduce estrogen load and resolve estrogen dominance symptoms such as menstrual cramps, endometriosis and uterine fibroids. They are invariably surprised post surgically if the desired clinical result is not achieved. Those who carry a lot of adipose tissue or are under stress (when the adrenal glands are put in overdrive) may continue to experience estrogen dominance symptoms post surgery as their adrenal glands continue to put out estrogen when under stress. Similarly, those who are obese face a continuous release of estrogen into the body, flooding the estrogen receptors.
    • Estrogen and progesterone are hormones that complement and oppose each other at the same time. The clinical presentation depends on many factors, including receptor health. Both symptoms of estrogen dominance and estrogen deficiency can be similar and confusing to those who are not clinically alert. Too much or too little estrogen can lead to vascular instabilities or hot flashes. Those who are under stress with high adrenal function and obese are most at risk for estrogen dominance. On the other hand, those who are thin and petit in size tend to be suffering mostly from estrogen deficiency, though clinically they both present with hot flashes as well. Not to be forgotten are the roles ERs and PRs play with their co-activation and co-repression properties in this hormonal symphony in terms of amplification of the hormonal response. The degree and varied response possible is almost infinite. It comes as no surprise that hormone manipulation is more an art than absolute science clinically.
    • Route of hormone administration is another determining factor of clinical outcome. Both natural and synthetic estrogens and progesterone used in therapy are well absorbed by the oral route, but they are subject to strong first-pass metabolism in the liver. Much less is needed to reach the receptor sites to give the same effect if they are administered transdermally or sublingually. Furthermore, the speed of expression by transdermal application through fatty tissue such as the abdomen will have a slower release as compared to blood vessel rich areas like the neck or wrist.

    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.

    Receptor Disorder Alerts

    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:

    • The body is fragile and behaves in a finicky manner. Some days, select nutrients can bring positive responses. Other days, the opposite can occur.
    • Hypersensitivity to drugs or supplements in general. For example, taking melatonin at night before sleep might cause a hangover the next morning.
    • Paradoxical responses to drugs or supplements, such as magnesium causing an alert reaction instead of the normal calming effect
    • Blunted responses to drugs and supplements. For example, increase in thyroid medication dosage is needed over time for no apparent reason.
    • Consistent low body temperature that fails to increase with increased thyroid replacement.
    • Progesterone triggering estrogenic effect for no apparent reason.
    • Slower onset of drugs to reach therapeutic effect compared to normal.
    • Amplified response to supplements. For example, a small amount of vitamin C can trigger significant increases in energy and cause a wired feeling.
    • Presence of history of organ resistance, such as thyroid or insulin resistance.
    • Small framed and thin women presenting with chief complaint of hot flashes.
    • Failure of fatigue to improve in AFS after cleaning the extracellular matrix and liver decongestion.
    • Exaggerated response to small amounts of thyroid medication.
    • Unable to tolerate birth control pills requiring many adjustments.
    • Unable to tolerate hydrocortisone and feeling worse on it.
    • Reduced ability or unable to tolerate herbs and glandular supplements.

    Sufferers of Adrenal Fatigue should be on the lookout for any symptoms or signs that may be associated with receptor disordersRemember 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.

    Receptor Support Tips

    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:

    • If history points to receptor dysfunction, a confirmation trial should proceed first and foremost. For example, if estrogenic heterologous desensitization response by progesterone is suspected, one can discontinue progesterone and see if the symptoms go away. This is then followed by re-introducing progesterone after a rest.
    • Once receptor dysfunction is confirmed clinically, take alternative therapeutic routes to achieve clinical improvement. Bypass activation of the receptor in question and associated biochemical pathways to all the receptor system to rest. For example, if there is suspected thyroid resistance due to AFS, take time to heal the AFS rather than forcing more thyroid onto the receptors. Thyroid receptors will have some time to heal themselves. We are often surprised at how well the thyroid receptors are able to cope with medication once the adrenals are healed though they were not able to do so previously.
    • Focus on liver and extracellular matrix decongestion as ways to augment receptor site healing and recovery. Those two are subtle but powerful deterrents to speedy recovery.
    • Concentrate on giving the body the raw materials to help it built hormones and receptor sites. This way, the body’s feedback loops are intact. For example, if more dopamine is needed, one can consider giving the body more tyrosine, its precursor. Similarly, thyroid hormone production can be enhanced with iodine, and cortisol production can be enhanced by a combination of Vitamin C and B5. Forcing external hormones, such as cortisol, into the body over the long-term may lead to a state of lazy adrenals because the body no longer has to be on its toes everyday to modulate the necessary hormone. Feedback loops not used can be down regulated.
    • Do not force nutrients into the body before receptor sites are healed and strong. Repair takes time. Forcing nutrients before the body is ready will only burden it at a critical time, triggering retarded recovery and possible crashes.
    • Clinical correlation with laboratory values of other parameters if available must be done. Focusing on laboratory values alone is often confusing and can be misleading.
    • 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.

    • Expect the progress to be slow. Make sure your expectations are reasonable. Do not get frustrated, as that will only retard the recovery process. Periodic setback is expected. The overall recovery curve should be gradual improvement over time, though it is not unusual to see no significant clinical improvement for the first three to six months. Often times the body needs a few months to reset and prepare, so to speak. Cellular regeneration is a slow process. We have to be patient and stay focused providing the tools needed for Mother Nature to do her healing.
    • Close monitoring is required. As receptor function changes, the body’s symptoms will change greatly. Previously administered nutrients usually need to be adjusted in terms of dosage, delivery system, and frequency to match the body’s state of function each step along the way. For example, as thyroid function improves, less thyroid support will be needed in order to avoid hyperthyroidism.
    • Look at this as an opportunity to learn and mentally embrace your receptors rather than as a curse. Practice positive psychology to enhance recovery speed. There will be periodic setbacks. Learn to recognize signs and symptoms of a body becoming overburdened during the recovery process. Stay in close touch with your health professional. Managing setbacks are important to avoid adrenal crashes along the way.
    • As receptor site function improves, gentle challenges should be administered regularly to get a feel of receptor health and resilience. This will provide insightful entry points for nutrients and medication adjustments.


    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.

    © Copyright 2015 Michael Lam, M.D. All Rights Reserved.