Receptor Disorders and Adrenal Fatigue Syndrome – Part 2

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

Read Part 1

Let us now look at how key hormones of Adrenal Fatigue Syndrome interacts with their receptors.

Cortisol Receptors Disorders

Adrenal Fatigue and cortisol are intrinsically linked to one anotherWhen 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 in Adrenal Fatigue

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.

Adrenal Fatigue sufferers may have one or more receptor disorders within their bodyReceptor 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.

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

Dr. Lam’s Key Questions

Abstinence is the best birth control, you can also use condom and diaphragm because these do not introduce additional hormones into your body.

You can improve your OAT axis imbalance to start. If symptoms still persist, you may seek guidance from PMD. Taking DHEA or pregnenolone may help to increase testosterone also.

Adrenal Fatigue sufferers may have one or more receptor disorders within their body