Adrenal Fatigue – Enhancing Quality of Life for Patients with a Functional Disorder *

Authors: Chris D. Meletis, N.D., and Wayne A. Centrone, N.D., A.T.-C.

The human organism is bombarded with an incredible variety of stresses at any given time. Stress can be categorized in an equally dizzying number of ways. There are both chronic and acute stressors. There are somatic stressors that push the body away from homeostasis. There are psychogenic stressors that seem to be triggered at the slightest provocation. An elaborate system of hormones and neurotransmitters (coupled with the human penchant for becoming upset about nonphysical stressors) engenders psychogenic stress in human beings more than in any other species of animal.*

There are two basic kinds of psychogenic stress (1) rational (fear) and (2) irrational (anxiety). Regardless of the nature of the stress — mental or physical, rational or irrational—the body responds to all stress in a fairly predictable manner. In the early 1930s, Selye1 termed this predictable pattern of response the general adaptation syndrome. Both conventional and nutritionally oriented health care providers principally utilize and share the same biomedical model of stress and its physiologic effects. However, the two schools of practice diverge when it comes to diagnostic methodologies that are used to identify subclinical cases of adrenal dysfunction and the modalities used to treat these patients.

How the Adrenal Glands Respond to Stress

At the center of the stress response are the adrenal glands. The adrenals produce epinephrine and norepinephrine, along with other hormones such as cortisol that enable the body to adapt to and survive a stressor. The acute alarm, or immediate reaction to a stressor, is a physiologic phenomenon in which the sympathet­ic nervous system responds to exogenous or endogenous stres­sors put the body into what is popularly called the “fight, fright, or flight” mode. When the body is in this state, such as in poten­tially life-threatening situations, adrenal hormones are released to increase heart rate and blood pressure and divert blood to the brain, heart, and skeletal muscles. This physiologic compensation is a key mechanism in stress and the clinical phenomenon of adrenal fatigue.

The adrenal cortex produces steroid hormones, which include cortisone, hydrocortisone, testosterone, estrogen, 17-hydroxy­ketosteroids, dehydroepiandrosterone (DHEA), DHEA sulfate, pregnenolone, aldosterone, androstenedione, progesterone, and other intermediates to hormone production. These are the most widely studied of the stress-related hormones. Although most of these hormones are created in different parts of the body, aldos­terone, cortisone, and hydrocortisone are produced only in the adrenal glands.

Aldosterone, working in cooperation with the renal system, helps to regulate the balance of sodium and potassium in the body. This regulation is critical to many physiologic functions, including the ability to react to stress and to maintain fluid bal­ance. This hormone also contributes to the maintenance of blood pressure. In “adrenal fatigue” states, patients may have alter­ations in the fluid-balancing mechanism, with the most com­monly described symptom being “puffy hands and feet.”

Recent conventional medical research has shown that subclini­cal adrenocortical disease can exist without adrenal function fail­ure.2 The etiology of this subclinical disease process has not been elucidated fully in conservative research. Authors who write for alternative medical periodicals and texts have historically expressed a belief that severe, long-term stress can lead to a clini­cal phenomenon known as “adrenal burnout.”3,4

Most individuals adapt to the stresses of life and, when these stressors are reduced, these patients experience favorable psy­chophysiologic responses, demonstrating the correlation between stress and physiologic functioning.5 Being unable to adapt to stressors can manifest as “staleness syndrome” or adrenal dys­function.3,4,6 Individuals who experience this disorder are unable to perform at their customary levels of activity at the office or home. They seem to suffer from persistent deterioration in their everyday functioning and activities. Indeed, depression and a marked decrease in performance seem to be the hallmark of this maladaptation syndrome.7,8

Biochemical Reactions to Stressors

The fight, fright, or flight response to stressors involves the cat­echolamines, substances that prepare the body for a call to imme­diate action and response, by causing short-term hyperglycemia. This rapid catabolism of blood glucose is the result of liver-glyco­gen storage breakdown and anincreased rate of gluconeogenesis. Catecholamines can also liberate rapid stores of energy by catab­olizing fat from adipose tissue stores.

The stress adaptationphase primarily involves glucocorticoids, released by the adrenal cortex, that have a profound effect on energy metabolism and biologic functions. These substances raise blood-sugar levels, increase muscle-protein breakdown and hep­atic gluconeogenesis, and mobilize fatty acids.9 Following nor­mal diurnal patterns for the release of serum cortisol, glucocorticoid levels are at their lowest point at approximately midnight to 1 AM. Peak levels occur between 6 AM and 8 AM. Research has shown that elevation or suppression of daily corti­sol levels indicates imbalanced hepatic–pituitary–axis (HPA) activity.10 This may be interpreted as hyperfunction or hypo­function, depending on a patient’s levels of cortisol and his orher clinicalpresentation.

Sustained activation of the sympathetic nervous system marks the compensation stage, also known as the adrenal hyperfunction stage, with a secondary influence on the HPA axis. The pituitary gland responds to the influence of sympathetic nervous system activity by releasing adrenocorticotropic hormone (ACTH). In turn, the adrenal glands respond to the pituitary release of ACTH by producing excess cortisol and androgen hormones.

In an attempt to compensate for this faulty hyperfunction, the hypothalamus–pituitary axis becomes less sensitive to the influ­ence of cortisol’s feedback inhibition. As serum cortisol levels rise, glucose utilization declines and insulin resistance increases, gluconeogenesis in the liver increases, and blood glucose levels increase rapidly. In addition, the body responds to increased cor­tisol by increasing the degradation of protein stores to supply amino acids for gluconeogenesis in an attempt to mobilize ener­gy rapidly.

Adrenal hyperfunction can be marked by a tendency toward insulin resistance, hypertension, mild obesity, and elevated serum lipid and triglyceride levels. What is more, high cortisol and lowered DHEA have been shown to suppress the immune system.11 Histologic studies have revealed lowered production

of secretory immunoglobulin A (sIgA) in the mucus membranes of competition swimmers under the influence of chronic levels of physiologic and psychologic stressors. At this phase of the stress response, athletes and other individuals will often complain of a decrease in performance or work production and a generalized feeling of lassitude.

The final stage of the stress response is the adrenal hypofunc­tion stage or the fatigue stage. The body’s ability to synthesize cortisol and other corticosteroid hormones is greatly diminished. The resulting excessive fatigue, changes in a person’s ability to concentrate, inability to tolerate alcohol, intractable headaches, lowered blood pressure, menstrual irregularities, reactive hypo­glycemia, and carbohydrate sensitivity may follow.12 With this compromised ability to control inflammation, the body goes into a pro-inflammatory state. The absence of cortisol leads to an increase in endogenous inflammatory eicosanoids and cytokines and leads to eventual tissue damage and degenerative disease.13


Botanicals for Treating Adrenocortical Dysfunction

Botanical agent RX Mechanism of Action
Licorice (Glycyrrhiza glabra) 1-2 g per day (max 30 g per day) Suppresses 5-b –reductase activity; may cause blood pressure elevations requiring monitoring
Hog Weed (Boerhaavia diffusa) Unknown Buffers plasma cortisol elevation; reverses adrenal cortisol depletion under high levels of stress
Ashwagana (Withania somnifera) 10–60 drops tid–q.i.d of fresh plant-liquid extracts Glucocorticoid-like effects from plant sterols
Siberian ginseng (Eleutherococcus senticosus) Dry strength liquid extract: 20–60 drops q.d.–q.i.da Binds to mineral-and glucocorticoid-receptors

aTilgner S. Herbal Medicine: From the Heart of the Earth. Cottage Grove, OR: Wise Acres Press, 1999.

Effects of Stress on the Body

We often hear of 30-year-old marathon runners who are forced into early retirement because of recalcitrant tendonitis. Are these simply cases of poor biomechanics and faulty training plans? Or are these athletes suffering from a maladaptation syndrome in which their bodies can no longer compensate for massive levels of exogenous and endogenous stress (work, family responsibili­ties, exercise, etc.)? Uncontrolled stress strains the entire organ­ism. Stress increases the metabolic rate, resulting in the mobilization of stored energy sources and the eventual break­down of muscle protein to make up for energy shortfalls.14 In short, the body attempts to maintain homeostasis at all costs.

Extended bouts of stress, such as high-volume exercise, psy­chologic stress, or other lifestyle challenges, lead to abnormal increases in serum cortisol levels and irregular circadian rhythm variations in cortisol secretion.15 Sustained elevated levels of cor­tisol may lead to reduced adrenal responsiveness to ACTH.16 This is compensated for by increases in pituitary releases of ACTH in the initial stages of overtraining. However, protracted stress causes pituitary release of ACTH to decrease and, thus, the pituitary gland becomes underresponsive to stimulation. The ultimate effects of prolonged elevated levels of cortisol are sup­pression of corticotropin-releasing hormone and ACTH release and atrophy of the zonae fasciculata and reticularis as a conse­quence of ACTH deficiency.17 Finally, the HPA axis fails to respond to stress and stimulation.18 This clinical measurement of suppressed endocrine function may be the defining element in the accurate identification and appropriate treatment of chronic “overstress syndrome.”19

Overuse of Corticosteroids

Cortisone and hydrocortisone help to regulate the body’s glu­cose. Since the late 1940s, corticosteroids have been used medi­cally to alter and suppress immune function. With a phenomenal range of applications, corticosteroids were quickly adopted as “miracle cures” for the full range of autoimmune diseases,

including the difficult-to-manage rheumatoid arthritis. However, it did not take long for clinicians and researchers to discover that there was a severe cost for chronic corticosteroid use. Countless patients developed physical conditions that prior to such widespread use of these agents were rarely seen by practitioners of Western medicine. Cushing’s syndrome, an overt hypercorti­solemia disease, became the price a patient paid for poorly moni­tored corticosteroid administration.

Diagnosing Adrenal Dysfunction

The fine homeostatic balance between health and disease can be disturbed if the clinical cause of a patient’s original imbalance is not fully explored and treated. Indeed, replacement or augmenta­tion of hormones from exogenous sources, all too often, merely suppresses symptoms while leaving the underlying disease pro­cess to advance without the diagnostically helpful symptoms.

When addressing adrenal imbalance, it is essential to look beyond laboratory tests and symptoms alone and to integrate the clinical presentation as a whole. Just as overt signs and symp­toms of thyroid dysfunction may or may not always manifest with abnormal laboratory tests, a functional adrenal condition may be present in the absence of abnormal laboratory findings. In fact, a recent plethora of medical literature points to the seem­ingly error-prone assessment that results from measuring thyroid function solely via laboratory tests.

The main cause of adrenal fatigue is continual low-level stress, which taxes the adrenal glands, limiting their ability to adapt to acute stressors. This low-level stress may be caused by emotional or physical upsets orloss of sleep. Clinically, this manifests in the development of exhaustion that does not become resolved with standard rest and relaxation.

A large number of symptoms associated with adrenal dysfunc­tion have been reported in the literature. These symptoms are often categorized according to physiologic performance, psycho­logic/information processing, and immunologic and biochemical parameters.20 To date, however, there is no universally agreed-on group of symptoms that describes accurately the condition or the physiologic/psychologic/emotional distresses that some peo­ple experience. Rather, multiple symptoms may present in no particular combination under the general categories of adrenal exhaustion, hypoadrenocorticalism, and hyperadrenocorticalism.

Perhaps the most confusing and controversial clinical compo­nent of diagnosing and treating adrenal imbalance is codifying the testing parameters to determine conclusively the presence of adrenal exhaustion and dysfunction.

To advance alternative medicine in evidence-based clinical practice, tools must be developed that can give practitioners a comprehensive approach diagnosing adrenal burnout syndrome. By combining biochemical studies, endocrine assays, and physio­logic functioning tests, these assessment methods would allow a clinician to gain a greater understanding of a patient’s stress response. Numerous assessment methods have been proposed and are utilized to measure and track adrenal dysfunction. Some of these testing models are listed below.

The24-Hour SalivaryCortisol Pattern

Thispatternconsistsoffourpoints—7 AM–8 AM,noon,4 PM–5 PM, and 11 PM–midnight. Research suggests that measur­ing salivary, as opposed to serum cortisol and DHEA, levels may be the best indication of adrenal function.21–24 Yet con­troversy exists concerning the complete validity of such test­ing methods because of potentially confounding variables, such as dietary interference, diurnal variations in salivary production and viscosity, oral contaminants, and the potential presence of gingival disease or problems regarding the mouth ecology.

The 24-HourUrineFree-HormoneProfiles

ACTHs are part of a complex pathway of biochemical messen­gers. It is, therefore, difficult to identify where, exactly, in this “pathway” dysfunction may be occurring. In response to this complexity, comprehensive testing laboratories have developed methods for evaluating primary and secondary steroid hormones and their most important metabolites. This provides practitioners with a tool to examine the stress response more fully in the con­text of overall hormonal balance including precursors and metabolites of the hormones.25 sIgA

A protein modulator of immune activity, sIgA is intimately linked to the activity of the autonomic ner­vous system. Alterations and dys­functions in the autonomic nervous system can be measured directly by changes in salivary composition and excretion. Medical researchers have recently theorized that factors such as exercise and chronic stress might induce changes in several components of saliva, such as immunoglobulins and proteins.

Plasma Glutamine

Glutamine is considered to be a conditionally essential amino acid because it can be synthesized in the body from glutamic acid. Glutamine is an important modulator of many homeostatic functions and optimal functioning of specialized tissues within the body. These tissues are key to gut and immune system func­tion. Researchers have recognized certain conditions in which the body’s demand for glutamine exceeds its ability to synthesize it. Such conditions are associated with high levels of physiologic stress. Under such chronic, catabolic conditions, the body takes its supply of glutamine from muscle tissue.26

Total Blood Cholesterol

Researchers theorize that because the body alters its ability to compensate for a shift in adrenal function, stress has a deleteri­ous influence on cholesterol synthesis and specific lipoprotein molecules. Measuring total body cholesterol will allow researchers to correlate changes in adrenal function with shifts in cholesterol levels.

Serum Ferritin

Ferritin reflects the body’s iron stores and is a good indicator of iron storage status. The ferritin test is more sensitive than the iron or total iron binding capacity test for diagnosing iron defi­ciency or overload. Measuring ferritin levels will provide an additional means of assessing immune function and physiologic adaptationto stress.

Morning Basal Body Temperature

Cortisol has a profound suppressive effect on thyroid-axis function. In the presence of elevated cortisol, thyroid functioning can become significantly impaired. The resultant changes in thy­roid metabolism can include suppression of thyroid-stimulating hormone (thyrotropin; TSH) and decreased conversion of thyroid hormone from thyroxine (T4) to the more potent form of tri­iodothyronine (T3) in peripheral tissues. It has been hypothesized that these effects arise from inhibition of the enzyme 5-deiodi­nase, affecting the T4-to-T3 conversion and suppression of TSH by endogenous somatostatin.

Postural Muscle Assessment

Research has identified restricted muscular sodium/potassium

adenosine triphosphatase (ATPase) activity and reduced cortisol levels in chronically stressed rats. Studies suggest that it is necessary to have an “intact pituitary–adrenal axis for adequate function of the sodium/potassium pump.”27,28 An ion shift with an increased extracel­lular potassium concentration has also been proposed as a possible cause of muscular complaints dur­ing exercise in patients who use b -blockers. Postural muscles (gas­trocnemius, soleus, medial ham­ strings, short adductors of the thigh, hamstrings, psoas, piriformis, tensor fascia lata quadratus lumborum, erector spinae, latissimus dorsi, uppertrapezius, sternomastoid, levator scapulae, pectoralis major, and the flexors of the forearm) shorten under stress. Therefore, evaluation of the postural muscles may be an excellent clinical tool to assess a patient’s response to treatment.

Herbal Treatments for Adrenocortical Dysfunction

To compensate for increased stressors, many individuals have turned to ergogenic or energy enhancement substances. These herbal and nutritional supplements are thought to have some type of ergogenic activity and are among the best-selling natural products in nutrition stores, with a financial impact in the $2–3 billion per year range.

Although there is a body of scientific literature on a variety of natural ergogenic substances—such as pyruvate, creatine, ephedra (ma huang; Ephedrasinica), ginseng (Panax spp.), and guarana (Paullinia cupana)—using animal models, there are few well-designed human clinical trials. This paucity of legitimate research, and the high over-the-counter use of natural products suggest an urgent need to conduct studies on the long-term effec­tiveness and safety of these naturalergogenic aids.

Natural products (such as phytopharmacologic agents), which appear to enhance performance capacity (as demonstrated in ani­mal and human studies), include such nutrients as creatine and pyruvate and such herbs as guarana, ginseng, Siberian ginseng (eleuthero; Eleutherococcussenticosus), schisandra (Schisandrachi­nensis), and ashwaganda (Withaniasomnifera).29–31 Other botani­

cals with purported ergogenic efficacy include regular coffee (Coffeaarabica), cola nut (Cola accuminata), and ephedra. These herbs are thought to have ergogenic effects because they contain methylxanthine compounds (cola nut and coffee beans), which have been shown to mimic the effects of endogenous epinephrine (ephedra). Caffeine, a methylxanthine, has been shown, in human trials, to enhance endurance and exercise performance.32

Perhaps the most misunderstood of all adrenal tonic herbs, are the adaptogens. The term adaptogen, coined by Brekhman, was proposed as a more appropriate description for isolated phyto­chemical compounds. Adaptogens, first identified in 1966 by Brekhman, are, collectively, a group of medically effective sub­stances that put organisms into nonspecific heightened resistance states to help organisms to combat stressors and adapt to extraor­dinary challenges.

These herbs are of most interest to nutritionally minded physi­cians as substances that can enhance an individual’s resistance to the long-term, cumulative effects of high-volume and high-inten­sity stress (such as exercise).

Perhaps the most studied of the adaptogenic herbs are Siberian ginseng and licorice (Glycyrrhizaglabra). Their purported mecha­nism of action is to reduce the amount of hydrocortisone broken down by the liver, thereby reducing the workload of the adrenal glands. These herbs were the first to be studied as adaptogens. Additional first-generation adaptogens include schisandra and reishi (Ganodermalucidum). 33

There are additional botanical agents that have been reported to have adaptogenic qualities but these agents have not been studied extensively for their support of the adrenal system. These include: ashwaganda, gotu kola (Centella asiatica), wild oats (Avena sativa), astragalus (huang chi;Astragalus membrana­ceous), fo-tior hoshouwu(Polygonummultiflorum), burdock (Arc­tium lappa), and suma (Pfaffiapaniculata). There are other herbs that may be classified as adaptogens, but they are not yet fully understood and are not highly available in most Western nations.

In modern scientific research and clinical results, eleuthero is one of the rare herbal medicines that has been tested extensively on humans in clinical trials. Eleuthro’s adaptogenic and other protective and strengthening properties have been studied and confirmed with thousands of human volunteers. We can still learn much more about eleuthero, but researchers have already defined some of the ways in which eleuthero affects the body biochemically and have identified certain active constituents that are natural plant steroids, the eleutherosides.

Research has documented that holy basil (Ocimim sanctum) acts as an antioxidant and may decrease levels of stress hormones.34 This herb is a powerful anti-inflammatory that has an effective­ness that is similar to aspirin and ibuprofen. However, unlike aspirin and ibuprofen, this herb is not irritating to the lining of the gastrum. Animal studies have found that holy basil has simi­lar effects to a variety of mood-enhancing pharmaceuticals such as stimulants and antidepressants.

†The author has no vested interest in this product.

Botanicals with Purported Adaptogenic Properties

  • American ginseng (Panax quinquefolium)
  • Ashwaganda (Withania somnifera)
  • Astragalus (Astragalus membranaceus) root
  • Borage (Borago officinalis)
  • Bupleurum (Bupleurum chinense)
  • Cola nut (Cola nitida)
  • Devil’s club (Oplopanax horridum)
  • Echinacea (Echinacea spp.)
  • Ginseng (Panax spp.)
  • Licorice (Glycyrrhiza glabra)
  • Oats (Avena sativa)
  • Prickly ash (Xanthoxylum clava-herculis) bark
  • Siberian ginseng (Eleutherococcus senticosus) Scullcap (Scutellaria lateriflora) Suma (Pfaffia paniculata) Turmeric (Curcuma longa)

From: Tilgner S. Herbal Medicine: From the Heart of the Earth. OR: Wise Acres Press, 1999.

Nutraceuticals for Treating Adrenocortical Dysfunction

Phosphatidyl serine (PS)isused to treat adrenocorticaldysfunc­tion. One product, Seriphos™ (Interplexus, Kent, Washington), provides a form of PS that does not depend on enzyme availabili­ty for gastrointestinal-tract absorption.35,† This product stimulates neuronal plasticity, acting as a compensatory adaptive mecha­nism to cell deterioration. PS is also capable of preventing or delaying the age-dependent decline of neurotransmitter function.

Some examples of additional nutritional agents use fortreating adrenocortical dysfunction comprehensively include: buffered forms of vitamin C, vitamin B-complex formulas, pantothenic acid, zinc, lipoic acid, and glandular extract supports (also known as protomorphogens or adrenal cortex extracts).

PS is purported to help in optimizing the stress response and repairing the damage wrought by catabolic stress hormones. Clinical studies have demonstrated that subjects experience improvement on computerized and standard neuropsychologic performance tests for sleep and mental function.35

The clinically common prescription of PS for optimal absorp­tion, is two capsules (250 mg each) taken before meals (at least 15 minutes before eating) or before bedtime. To mimic the diurnal effect of cortisol, holistic health care practitioners recommend tak­ing two capsules in the morning and two during midafternoon.


A particularly interesting study revealed that cortisol strongly fluctuates with increases and decreases in negative affect. The parameters of this research included testing salivary cortisol lev­els of 30 healthy young men experiencing an activating and humorous video, a speech stressor, and a resting control. The study researchers found that negative affect increased during the speech but strongly decreased during the video. The researchers concluded that their results suggested that the HPA axis is a dynamic system that is influenced by changes in negative affect independently of the experience of generalized activation.36

An increasing amount of research points to the relation between emotional states and sympathetic nervous system over­activity.2,37 This research confirms that the mind and body can no longer be looked on as separate moieties. Whatever the under­lying mechanism that connects mind and body, the writing on the wall is quite clear—medicine can no longer separate the structure of the human body from the function of the human body. Ultimately, as we have known for a very long time empiri­cally, restoration of homeostasis requires treatment of the whole organism, not just one part of it.38

With regard to adrenocortical function, even on the purely physical level, many physicians who practice nutritionally orient­ed medicine have noted that certain conditions improve with treatment for adrenal fatigue. Some of the more common condi­tions that respond to this kind of are acute viral illnesses, aller­gies, gastritis, osteoarthritis, rheumatoid arthritis, eczema, contact dermatitis, urticaria, psoriasis, and allergic rhinitis.


*Sapolsky R. Stress and disease: Who gets sick and who stays well. Insti­tute for CorTexT Research and Development, Stanford University, Department of Biological Sciences and Neuroscience. Spring 1995lecture.

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