Categories: Adrenal Health

Receptors and Adrenal Gland Disorders

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). This article covers how adrenal gland disorders can affect your receptor sites.

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, especially with adrenal gland disorders

Biochemical Activation

A bioactivation and signaling journey converts information of our surroundings, outside the body, into cellular chemical 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 doorstep of the target organ, target receptor function acts as a gatekeeper and dictates how hormones outside the cells are converted into biochemical signals inside the cell for a call to action. Receptor function is the final gateway for completing the signaling 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.

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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

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.

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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 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.

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 and avoid adrenal gland disorders. 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.

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 gland disorders such as Adrenal Fatigue Syndrome are 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.

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As mentioned earlier, optimum hormonal homeostasis within the body depends on three main factors working in unison—hormone, receptor sites, and feedback loops.

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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.

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.

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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.

Adrenal Gland Disorders Summary

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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© Copyright 2014 Michael Lam, M.D. All Rights Reserved.

By: Dr. Michael Lam, MD, MPH; Dr. Justin Lam; Dorine Lam, RDN, MS, MPH


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