Receptor Related Disorders and Adrenal Fatigue Syndrome – Part 1

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). 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.

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 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.

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 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:

  • 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 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.

Laboratory Studies on Receptor Related Disorders

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.

Receptor Related Disorders

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

  • Parkinson’s disease (PD) is a common progressive neurodegenerative receptor related 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 receptor related disorders or syndromes bound by the common mechanism of central sensitization (CS) involving abnormal hyper excitement of the central neurons. Examples of these receptor related disorders includes fibromyalgia syndrome, chronic fatigue syndrome, irritable bowel syndrome, restless leg syndrome, myofascial pain syndrome, multiple chemical sensitivities, and posttraumatic stress disorder. Some adrenal gland disorders such as Adrenal Fatigue Syndrome (AFS) may fall into this category.
  • A defect in G protein is a receptor related disorders that can activity 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. Receptor related disorders or 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 closely known 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 receptor related 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 related disorders can lead to disorders of calcium homoeostasis.
  • Insulin receptor gene mutation receptor related disorders 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

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.

Negative Feedback Loops

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

Response-Driven Feedback Loop

The adrenal glands are key structures in the process of Adrenal FatigueThis 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 Loops

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?

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.

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 Related 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 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.

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© Copyright 2016 Michael Lam, M.D. All Rights Reserved.

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