Adrenal Maladaptation Syndrome

A Sweet Solution For Coping With Stress

Ward Dean, MD

Stress is a defining aspect of life — everybody has it, and everybody talks about it, yet few people are able to define what stress really is. Scientifically, stress is defined as the nonspecific response of the body to any demand made upon it (Selye, 1974). When stress becomes excessive, is damaging or unpleasant, we then properly refer to it as “distress.” Consequently, when we say someone is “under stress,” we usually mean excessive stress, or distress.

More important than finding a definition for stress is understanding the effect it has on our bodies. Stress-producing factors, or stressors, can be physical (work and exercise), biological (viral, bacterial and fungal), environmental (heat and cold), and situational (job, family, etc). And while there are numerous stressors, the responses they elicit from the body are very similar. It may be difficult to accept that such essentially different things as cold, heat, drugs, hormones, sorrow and joy could provoke identical biochemical reactions in the body. Nevertheless, this appears to be the case. It can be demonstrated scientifically that certain reactions to stress are totally nonspecific, and common to all types of stressors. Emotional stimuli are probably the most common stressors that most of us encounter in our daily lives—but they elicit the same physiological response that an encounter with a saber-tooth tiger did for our cave-man ancestors.

The Spice of Life

According to Professor Hans Selye, stress is “the spice of life.” Certainly a life free of stress and devoid of challenges would be filled with boredom and hardly worth living. The most memorable events in life tend to be those that are the most stressful — situations that require us to rise to a challenge and push past our normal limits. Asks Selye, “Who would enjoy a life of no runs, no hits, no errors?”

While it is important to recognize that excess stress can seriously affect human health, certain types of stress are actually good for us and can benefit our health. For example, most people today recognize the multiple physical and emotional benefits to be gained from physical exercise. Physicians once treated heart attacks with enforced inactivity. Now, we know that early resumption of physical activity (stress) is often the key to a successful recovery. Clearly, an issue for those looking to survive (and enjoy) the best in life is not how to avoid stress, but how to best manage stress.

How the Body Reacts to Stress

1. Neuroendocrine Adaptation Mechanisms

A key factor in the maintenance of resistance to stress is the hypothalamo-pituitary-adrenal axis. Stressors excite the hypothalamus to produce adrenocorticotropic hormone (ACTH) which induces the adrenal cortex to secrete glucocorticoids (principally cortisone) and DHEA, and the adrenal medulla to secrete epinephrine and norepinephrine. When cortisone levels rise, they inhibit the hypothalamus and pituitary, which in turn decrease CRH and ACTH production, respectively. When blood cortisone levels decrease, hypothalamic activity increases, releasing CRH. This increases pituitary ACTH output, which stimulates the adrenal cortex to increase blood cortisone levels. In this cyclic manner, equilibrium is maintained in the system.

Cortisone concentrations in the blood undergo cyclic, diurnal (circadian) changes. These changes are due to variations in CRH and ACTH output, as well as to changes in hypothalamic and CNS sensitivity to cortisol (these changes in hypothalamic sensitivity are very important). With normal diurnal rhythm, blood ACTH levels rise between 3 and 6 AM, causing increases in blood cortisol. Thus, blood cortisol concentrations are at their highest in the morning. These peak levels gradually decrease, dropping to minimal levels by night. Under normal conditions, basal morning cortisol concentrations are twice those at night.

Cortisone has been described by Dr. William Jefferies, author of Safe Uses of Cortisone as “the hormone of life,” as without it we would be unable to adapt to the various stressors of life. However, when produced in excess over a prolonged period, it has a number of adverse, damaging effects. These include elevations of blood sugar, sodium retention (resulting in hypertension), suppression of immunity, gastric ulcers, headaches, loss of bone density, and even heart attacks.

2. General Adaptation Syndrome (GAS)

The General Adaptation Syndrome (GAS) was first described by Selye in 1936. The GAS involves three progressive stages. The first stage is the alarm reaction, characterized by surprise and anxiety involved in dealing with a new situation. During the alarm reaction, the adrenal medulla produces epinephrine and norepinephrine—the “flight or fight” hormones. Also, the adrenal cortex is stimulated to produce additional hydrocortisone and related hormones.

The second stage is that of resistance, where we learn to efficiently cope with the stressor (adaptation). An ideal situation is one in which adaptation occurs and continues until the stressful situation resolves, with a rapid return to the resting state. However, just as any inanimate machine may wear out or break down whenever a heavier load than it is designed to tolerate is applied, so too does the human machine sooner or later become the victim of constant wear and tear. Unfortunately, our capacity for adaptation is limited. Also, everyone’s adaptational capacity (i.e., tolerance to stress) is different. What may “charge one person’s batteries” may totally devastate someone else. Consequently, the third stage of the GAS is that of exhaustion, involving a depletion of our energy reserves and loss of adaptational ability, leading to fatigue, or other symptoms or diseases.

Just as a chain breaks at its weakest link, so too can exhaustion of our adaptive capacity result in stress-induced disease. This stage of adrenal exhaustion is also sometimes referred to as the adrenal maladaptation syndrome, or hyperadaptosis (Dilman and Dean, 1992). Adrenal dysfunction may be manifest by (1) an excess or inadequacy of cortisone, DHEA, ACTH and/or CRF; (2) relative imbalances of these hormones and releasing factors, or (3) loss of sensitivity of the hypothalamus and pituitary to the normal inhibiting effects of these hormones.

Stress and Aging

As we mentioned previously, stress is the nonspecific response to any kind of demand at any one time. The sum of all the stresses to which the body has been exposed during a lifetime can contribute significantly to the ravages of aging. A good example of the age-accelerating effects of stress is how President Jimmy Carter literally aged in front of our eyes as he tried to cope with the Iran hostage situation.

The main difference between aging and The General Adaptation Syndrome (GAS) appears to be that the GAS is more or less reversible if one is provided with adequate rest or therapeutic intervention, using either nutritional supplements or pharmaceutical drugs. But we must keep in mind that as long as we live we are always under some measure of stress, and that although excessive stress and aging may be closely related, they are definitely not identical. Professor Vladimir Dilman, my co-author of the Neuroendocrine Theory of Aging and Degenerative Disease (unfortunately, now out of print, but under revision), said that aging itself is a stressor.

Symptoms and Diagnosis

Individuals subjected to great stresses may develop adrenal maladaptation syndrome. In these instances, the glands work beyond their capacity, passing through the alarm reaction, the stage of resistance, and finally reaching the stage of exhaustion. Adrenal maladaptation syndrome may cause a variety of symptoms, depending on which organ system is the “weak link” in the chain. Some of the most common symptoms are listed in Table 1. Symptoms are often similar to those found in persons who suffer from hypoglycemia, hypothyroidism, chronic fatigue, and fibromyalgia.

Prior to treating someone with thyroid for suspected hypothyroidism, it is important to first determine whether there is some adrenal involvement. Supplemental thyroid given to patients who are both hypothyroid (low thyroid) and hypo-adrenal, who are not first provided with adrenal support, will often suffer from a worsening of their symptoms. However, despite this warning in the Physician’s Desk Reference (“Thyroid hormones are generally contraindicated in patients with uncorrected adrenal cortical insufficiency.”), it is an extreme rarity for physicians to evaluate adrenal function prior to prescribing thyroid hormone replacement.


Diagnosis of the Adrenal Maladaptation Syndrome is usually based first on the presentation by the patient with one or more signs and/or symptoms listed in Table 1. Often, treatment is initiated on an empirical basis, with no further testing, since the treatment is relatively benign and the likelihood of improvement so high. Although there are a number of blood tests that may contribute to the diagnosis, recently an innovative salivary hormone test has been developed that tracks not only the time-related changes of the levels of DHEA and cortisone, but also the DHEA/cortisol ratio as well. This test provides objective information on which to base the optimum therapeutic program.

Treatment of Adrenal Maladaptation Syndrome

While even scientists who have extensively studied the adrenal maladaptation syndrome may disagree as to whether it is due to too much or too little production of hormones from the adrenal cortex, or perhaps from too high or too low production of ACTH or CRF—what these scientists do agree on is that all of the symptoms are due to an alteration of the performance of the hypothalamus and the adrenal cortex—and these apparently diverse conditions surprisingly often respond to the same therapy.

First, in any condition characterized by adrenal dysfunction, I believe it is extremely important to stabilize blood sugar—whether it is too high or too low—thereby alleviating a major metabolic stress on the body. Consequently, I generally recommend a “zone” type diet in these cases, i.e., one that emphasizes protein and fat, and restricts the amount of carbohydrates—especially refined carbohydrates. Also, I recommend numerous small meals or nutritious snacks throughout the day.

Second, exercise is probably one of the best “stress fighters” there is, and should be incorporated into the program. This does not have to be a six mile jog or a session of heavy weight lifting. Even when fatigue is so extreme that it is difficult to get out of bed, many people find that taking a walk around the block has a tremendous energizing effect.

Third, nutritional and/or pharmacological support to restore (1) hormone balance and (2) hypothalamic sensitivity to inhibition by glucocorticoids (cortisone). Substances that may be of help to restore hypothalamic sensitivity include:

  • Phosphatidylserine (100-300 mg per day);
  • Melatonin (750 mcg-6 mg per day at bedtime)

Substances that may directly alter hormone levels and balance include:

  • Pregnenolone (10-100 mg daily in the morning);
  • DHEA (5-100 mg daily in the morning);
  • Hydrocortisone (5-20 mg daily in divided doses

Provision of adrenal support by the use of (1) low-dose hydrocortisone treatment (as outlined in Dr. William Jefferies’ book, Safe Uses of Cortisone, (2) intravenous adrenal cortical extract, or (3) nutritional supplementation with adrenal glandular supplements and/or glycyrrhizin—a food additive nutritional supplement that is extracted from licorice, which mimics the effects of hydrocortisone.

Glycyrrhizin — Natural Cortisol-Mimicking Extract From Licorice

It has long been known that moderate consumption of licorice has beneficial effects in a variety of diseases, including allergies, asthma, chronic fatigue, hypoglycemia chronic stress, inflammatory conditions, and other symptoms that are outlined in Table 1. Glycyrrhizin is the ingredient that is removed from licorice—[DGL (deglycyrrhizinated licorice)]—that enables people to benefit from the ulcer-healing properties of licorice without worrying about the dangers of excess cortisone. Glycyrrhizin is also the active ingredient in licorice which mimics the effects of cortisone, and from which licorice’s beneficial effect is obtained.

Glycyrrhizin (and its “cousin,” Cortisone), however, are like two-edged swords. In small to moderate doses, they can be very beneficial. In excess, they can cause a number of adverse side effects, including water retention, elevated blood pressure, and loss of potassium. Consequently, it is very important to use the minimum effective dosage of glycyrrhizin, and to use it intermittently as needed (usually, for no more than 6-8 weeks at a time). Periods of use of glycyrrhizin should be interrupted by two to three weeks of non-use. Many people find that taking 25-100 mg/day of glycyrrhizin provides significant relief of symptoms of chronic fatigue, fibromyalgia, and other conditions that are related to “adrenal exhaustion” or adrenal maladaptation syndrome. Many people find that taking 25-100 mg/day of glycyrrhizin provides significant relief of symptoms of chronic fatigue, fibromyalgia, and other conditions that are related to “adrenal exhaustion” or adrenal maladaptation syndrome.

In order to mimic the body’s normal rhythm of cortisol, we recommend that glycyrrhizin be taken first thing in the morning, approximately 30 minutes before breakfast, and another (usually smaller) dose (if needed) before lunch. With glycyrrhizin, as with many supplements—more is not necessarily better. Only the minimum dose that produces the desired effect should be taken.


1.Barnhart, Edward R. Physicians Desk Reference, Medical Economics, Oradell, New Jersey, 1991, 690.

2. Dilman, Vladimir, and Dean, Ward. The Neuroendocrine Theory of Aging and Degenerative Disease, The Center for Bio-Gerontology, Pensacola, Florida, 1992.

3. Jefferies, William, McK. Safe Uses of Cortisone, Charles C. Thomas, Springfield, Illinois, 1981.

4. Selye, Hans. Stress Without Distress. Signet, New York, 1974.

5. Tintera, John W. The hypoadrenal state and its management. New York State Journal of Medicine, 55: 13, July 1, 1955, 1-35.in rats. Indian J Med Res. 1990;92:471-5.

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