An effective veterinary model may offer therapeutic promise for human conditions: cortisol and thyroid hormones

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This article was published in the journal Medical Hypotheses in March 2003Summary For nearly three decades, the author has treated multiple serious diseases of cats and dogs by correcting an unrecognized endocrine-immune imbalance originating with a deficiency or defect of cortisol. The cortisol abnormality creates a domino effect on feedback loops involving the hypothalamus-pituitary-adrenal axis. In this scenario estrogen becomes elevated, thyroid hormone becomes bound, and B and T cells become deregulated. Diseases with this aberration as a primary etiological component range from allergies and strange behavior to severe cases of autoimmunity and cancer. Successful treatment and control, even in critical cases, have been consistently achieved with a long-term physiologic (not pharmacologic) replacement with cortisone along with thyroid hormone (in dogs). The treatment represents a major healing modality for many seemingly unrelated chronic diseases of animals. In humans, this endocrine-immune dysfunction appears to exist and, as in veterinary medicine, has been overlooked by researchers and clinicians. Testing and treatment patterned after the animal model may offer significant clinical benefits for challenging human afflictions.

INTRODUCTION

Years ago, as a new practitioner, the author became frustrated by the constant confrontation of canine and feline allergies and end diseases for which medical training provided little guidance other than for treating signs. In an attempt to understand causality and explore the possibility of more effective treatments he undertook his own clinical research.

In both young and old animals, similar problems were frequently found among littermates and along familial lines: severe hypersensitivity, widespread inflamed skin, ulcerations and itchiness, malabsorption, and internal systems out of control. The path of inquiry led to the strong suspicion that contemporary breeding practices - namely inbreeding and linebreeding for a fashionable appearance instead of for function and hardiness - were causing narrowed gene pools, compromised health, and shortened longevity.

For many conditions involving inflammation and itching, veterinary medicine commonly relies on an effective family of cortisol-type drugs (cortisone) for short-term therapy. As with human medicine, however, there is considerable reluctance about using these drugs long-term because of wellknown side effects. Even with this concern in mind, the author reasoned that cortisone therapy might in some way address an endocrine abnormality due to an unexplained genetic disturbance. Since cortisone is an adrenal hormone replacement, his attention turned to the adrenal glands.

Continued investigations indicated the presence of an unrecognized genetic flaw involving two of the three layers of the adrenal cortex and differing from the classic Addison’s and Cushing’s syndromes. Specifically, a problem in cortisol production was found that caused a significant and damaging domino effect on other hormones and the immune system. Cortisol, the primary adrenal glucocorticoid, is produced in the middle cortex layer. This critical hormone stimulates several processes that serve to increase and maintain normal concentrations of glucose in blood, exerts a potent anti-inflammatory effect, and acts as a regulating factor for normal immune function.

Cortisol is secreted in response to a single stimulator: adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH is itself secreted under control of the hypothalamic corticotropic-releasing factor (CRF). Cortisol secretion is suppressed or stimulated by classical feedback loops. When blood concentrations rise above a certain threshold, cortisol inhibits CRF secretion. This, in turn, inhibits ACTH and cortisol secretion (see Fig. 1).
However, when the adrenal gland is unable to produce enough cortisol, or for some reason the cortisol is bound, or otherwise inactive, and thus not recognized by the system, the pituitary continues to produce ACTH in order to extract more cortisol.

The inner cortical layer, where adrenal androgens are produced, also responds to ACTH. This zone produces the androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), substances known as prohormones in that they metabolize into other hormones, including the estrogen compounds estrone and estradiol.

The result of constant ACTH stimulation in a situation where cortisol is bound or deficient, appears through this conversion mechanism to introduce an excess of estrogen into the system. The estrogen activates a direct feedback on the hypothalamus. CRF is induced to stimulate the pituitary to release ACTH. This causes further release of estrogen-precursors from the inner layer adrenal cortex, raising the level of total estrogen in the system.

The influence of excess estrogen is a major confounding factor, causing the following: a "histamine-like" effect on capillaries, leading to inflammation from blood components spilling into adjacent tissue; binding of thyroid hormone and cortisol; and further deregulation of lymphocytes and antibodies (see Fig. 2).

The author relates the loss of critical immune system control to poor resistance and immune cells that cannot properly defend against viral, bacterial, and fungal infections, or protect the body against cancer. Moreover, the loss of regulation is probably related as well to autoimmune damage. Repeated clinical testing has shown that the endocrine imbalance described here coincides with abnormal levels of IgA, IgG, and IgM immunoglobulins.
There appears to be no discernible role in this endocrine-immune derangement of the outer adrenal cortical layer, where the mineralocorticoid hormone is manufactured. A deficiency of mineralocorticoid secretion, which governs sodium and potassium levels, is associated with Addison’s Disease. An excess of cortisol is the biomarker for Cushing’s Syndrome.

Cortisone preparations have many of the chemical actions of cortisol. They are, in fact, converted to cortisol in the body. The author reasoned that if the origination of the endocrine-immune imbalance stemmed from an inadequate supply of cortisol, and that therapeutic treatment with cortisone preparations reduced a significant degree of clinical signs, at least in the short term, perhaps long-term doses smaller than conventional pharmaceutical cortisone doses might be effective. In human medicine, Jefferies has used this approach for decades and reported improvement among patients with allergies, autoimmune disorders, and chronic fatigue (1).

After a trial-and-error period, the author developed a testing and treatment strategy that proved to be safe and highly effective. The central modality is replacement with physiologic doses of various cortisone preparations to address the root issue of cortisol deficiency/defect. This normalizes the activity of ACTH, stops the overproduction of estrogen and the blockage of thyroid, and reregulates the immune system (see Fig. 3). A second, important modality is the simultaneous use of thyroid hormone. This is necessary in all canine cases, and in about 10 percent of feline cases. The contrasting thyroid requirement between dogs and cats is an apparent species variation.

Elevated estrogen causes a binding effect on thyroid hormone. As a result, metabolic activity is retarded, including detoxification and the liver’s ability to process the cortisol replacement. In this situation, even physiologic doses of cortisone may accumulate in the body and create side effects. By giving cortisol and thyroid replacement simultaneously, the body is able to effectively utilize and process the former without side effects developing.

Once the hormone imbalance has been identified through a testing procedure described below, it is of paramount importance to initiate a hypoallergenic diet at the same time the hormone replacement program is started. The combination of daily feeding a commercial pet food, which typically has poor quality ingredients, and deregulated IgA in the digestive tract often leads to malabsorption and food allergies. The therapy program will not succeed if animals continue eating food to which they are sensitive. Within a few weeks, as animals improve on the program, pet owners can introduce different foods one-at-a-time back into the diet, but should stay alert for signs of sensitivity to specific foods.

In the late 1970s, the author wrote a series of reports in veterinary journals describing his findings and protocols (2, 3, 4, 5). As he uncovered these biochemical complexities in his research, he found no germane research in veterinary medicine to provide guidance. The comprehensive endocrine-immune abnormality described here has not been reported elsewhere, such as in major veterinary endocrine texts. However, many other genetic disorders among purebred pets, a result of contemporary breeding practices, have been reported (6).

In the beginning, the flawed endocrine-immune mechanism appeared to be involved as an aggravating factor, that is, exacerbating allergies and sensitivities to food and parasites such as fleas. But with time, and a proliferation of breed specific animals, gene pools have become narrower and narrower. The author and other veterinarians using his approach have consistently identified this mechanism in overt life-threatening diseases, such as severe autoimmunity and cancer. It appears not only to cause typical allergy problems but because of its deregulating impact on the immune system, also sets the stage for killer diseases. Younger animals with the defect are developing diseases previously seen only in older animals. Moreover, it often causes not just one illness but multiple disorders as well.

The research and clinical outcomes clearly show that this mechanism is a major factor in the etiology of common diseases. Associated diseases/disorders include malabsorption and digestive disorders, allergies, lung and urinary tract problems, sluggish liver function, strange or aggressive behavior, epilepsy, obesity, deadly viral and bacterial infections, periodontitis, vaccinosis, autoimmunity, and cancer.

The endocrine-immune derangement is not limited to purebreds. As affected purebreds have mated with mix breeds, the mechanism is now widely established among mixed breeds as well. Diseases primarily found in specific breeds years ago are now typically seen in many breeds and mix breeds. The defect has proliferated.
While the genetic impact appears to be the overwhelming causal factor for the imbalance, environmental inputs such as food intolerance, poor diet, sensitivities to parasites, toxins and stress, as well as aging, also enter into the equation.

Whatever the original cause, correction of the defect with appropriate levels of cortisone and thyroid as the main elements in a long-term hormone replacement and therapy program consistently helps even severely diseased animals to live long and healthy lives. When pet owners stop the therapy, for whatever reason, animals deteriorate. Signs of previous illness return. The therapy does not cure. It funds a deficit, realigns a hormonal derangement, resets the metabolism, and restores normalcy to a dysfunctional immune system. It controls disease and supports the health of the animal for as long as the program is maintained.

The author has personally treated more than 50,000 dogs and cats with this approach. In the U.S. and elsewhere, dozens of other veterinarians are using it successfully as well.

The author has also worked with interested equine veterinarians and breeders and found a widespread endocrine-immune defect present in horses. Many common equine ailments have been corrected using the criteria described here. In the case of horses, about 90 percent respond to thyroid replacement alone, while 10 percent require both thyroid and cortisol.

The volume of global clinical experience clearly indicates that animals who might otherwise be destined for euthanasia or a life of suffering can be effectively tested and treated. It is also clear that the endocrine-immune test described below can be used preventively to determine the presence of imbalance even in asymptomatic animals. The method thus defuses a ticking timebomb.

It is beyond the author’s capacity as a clinician to explore the molecular details of this problem. It remains his strongest desire to see the veterinary research community consider the findings. A thorough investigation into the widespread nature of this overlooked problem, and its genetic and biochemical background, is clearly warranted.

TESTING FOR THE ENDOCRINE-IMMUNE IMBALANCE

The endocrine-immune blood test developed by the author monitors a critical range of hormonal and immune relationships: cortisol, total estrogen, T-3, T-4, IgA, IgM, and IgG. The test is available to veterinarians through a commercial veterinary medical laboratory (National Veterinary Diagnostic Services, Quail Valley, California; phone 951-543-4678). Comprehensive tests such as these are not utilized routinely by veterinarians. They tend not to measure these levels and often prescribe steroids that may be too strong or not appropriate. This practice results frequently in side effects.

The test measures the impact of the HPA axis on the immune system. Cortisol itself, even if the value is normal, may be bound (inactive) to a various degree in different animals due to the nature of the genetic defect. This is why it is essential to look at the cortisol-estrogen-immunoglobulin relationships. The practitioner will recognize a cortisol problem if the estrogen level is high and the immunoglobulins are low.

Standard tests measure only one component of estrogen: estradiol. Total estrogen is a more accurate measurement, due to the fact that there can be varying levels present of the estrogen compounds. Estrogen can exert a dramatic blocking effect on cortisol and thyroid hormones, and just a slight variation out of the normal range is enough to cause hormonal and immune complications. In the presence of elevated estrogen, thyroid hormone may be bound up and rendered inactive to varying degree, enough to slow down overall metabolism, and trigger additional problems in the body. Considerable thyroid may in fact be inactive even if the thyroid values in the test are normal.

The critical value of this test to the clinician is that it offers a comparative view of endocrine-immune relationships. A singular hormone level found in the high normal range for one animal may be an inadequate level for another, while a low level for one animal might be too high for another. Each animal, like each human, is biochemically individual. Reading empirical levels alone, without considering the relationship of one hormone to another, or of one hormone to a system in the body, is like seeing only the trees but not the forest. In this case, the relationships are usually low cortisol, high estrogen, and deregulated immune cells. If the hormonal values in this test fall into the normal range, but if the animal is chronically ill and the immune cells are low, the therapy approach is the same, only the practitioner would use even less cortisone and thyroid than usual. Retesting after two weeks provides a gauge for determining the efficacy of the therapy. If the immunoglobulin values increase, and symptoms decrease, the course it correct. This is usually what happens.

Earlier, the author included T cell values in the panel. The mechanism described here also suppresses T cells. However, due to the significant added cost for this measurement, T cells were dropped from the blood test panel.

More than 90 percent of the cases treated by the author involve neutered animals. Thus, in the case of female animals, there is no influence of ovarian estrogen. Among the female dogs and cats with intact ovaries, testing and therapy are conducted when animals are not in estrus and not producing a high level of ovarian estrogen.

In summary, the test brings to light this overlooked cascade of pathology-causing effects:

The production of insufficient or inactive cortisol in the middle layer (zona fasiculata) of the adrenal cortex. If the cortisol is in the normal range, it may, however, be present in a largely bound form that cannot be used by the body. The presence of high estrogen and low immunoglobulins will indicate to the clinician that the cortisol is somehow inactive.
The presence of elevated estrogen, a result of stimulation of the inner cortical layer (zona reticularis) and apparent androgen-to-estrogen conversion. There is no relationship to cyclic ovarian production of estrogen.
Binding of thyroid hormone. This estrogenic effect can be ascertained by the following signs when both T3 and T4 test normal: excess sleeping; sluggishness; hyperkeratosis of the nose and pads of feet; excess pigmentation in skin of ventral abdomen; high cholesterol (not diet related); high triglycerides (not diet related); no increase in body weight; many patients are actually underweight.
A major deregulation and suppression of IgA, IgM, and IgG.

Animals are retested after two weeks and again at subsequent intervals, depending on the seriousness of the condition. Although improvements occur rapidly after a hormonal replacement program is initiated, retesting serves the clinician as a yardstick to gauge progress, evaluate normalizing endocrine-immune relationships, and consider possible adjustments in medication. The author uses a combination of pharmaceutical and plant-based cortisone preparations for patients, depending on the severity of disease.

True genetic imbalances require life-long management. Acquired imbalances can occur as a result of stress or exposure to toxic chemicals, anesthesia, heavy metals, or pollutants. They may require only temporary management but in some cases a lifetime of replacement therapy may be needed if symptoms return after therapy is discontinued.

APPLICATION FOR HUMANS?

Does this clinical research and therapy offer similar promise for humans?

Can cancer in humans be treated this way? The author has found the imbalance present in all animal cancer cases referred to him. Treatment outcomes are usually positive, even in advanced cases.

Can AIDS be treated effectively with long-term cortisone replacement? Feline immunodeficiency virus (FIV) is regarded as a similar retroviral agent as human immunodeficiency virus (HIV). The author has achieved a 70 percent success rate in treating felines with symptomatic FIV, who remain disease-free as long as they remain on the hormone replacement program. When a human is exposed to the HIV virus, whether or not he or she will "break" with AIDS, may depend on whether the endocrine-immune system is in balance. If the system is normal, or has been normalized through replacement therapy, the virus may be fully neutralized and rendered incapable of "causing" disease. The virus, in fact, may not cause the disease but rather over-stimulates a deregulated immune system. The reaction by the immune system then causes the disease.

Jefferies has reported in great detail on the safe and effective use of physiologic dosages of cortisone medication for a variety of human illnesses involving adrenocortical deficiency. This clinical perspective has been overlooked or dismissed by the vast majority of the medical community. In Jefferies words, the reason relates to the "unique situation in which a normal hormone, one that is essential for life, has developed such a bad reputation that many physicians and patients are afraid to use it under any circumstances." (7) This reason probably applies as well to a similar situation in veterinary medicine.

Jefferies believes that indefinite replacement with physiologic dosages of cortisone will benefit many, if not all, patients with chronic allergies and autoimmune disorders, and that replacement should not be stopped upon initial remission (8). Vast experience with animals clearly indicates that this is the right course of action. In the veterinary setting, if medication is stopped, the imbalance and symptoms return.

In the human setting, the author would further suggest that clinicians should test patients for the same range of hormonal-immune relationships as he does for animals. That means a blood test to measure cortisol, total estrogen, thyroid (T3/T4), and immunoglobulins. Other measurements could be added, such as T cells and perhaps other hormones, in order to develop a more precise picture of the defect’s total range of impact. Patients can be retested after biweekly or monthly intervals to monitor the changing relationships.

In the case of female patients, the clinician will have to take ovarian estrogen status into consideration. The level of total estrogen will change as a result of the cycle, pregnancy, whether the patient is perimenopausal or menopausal, or taking an estrogen replacement. A testing method will have to be structured that accommodates these individual situations. One approach for menstruating females might be to test in mid-cycle when the ovarian estrogen level is highest and again just prior to menses when it is at the lowest level. The clinician would compare the estrogen values against immune cell values.

In addition, the clinician might want to obtain a 24-hour urine sample from the patient in order to test for active T3, T4, and cortisol. This would be an important diagnostic tool allowing a comparison to blood values, which may test out as normal but in fact may involve a significant percentage of bound (inactive) hormone. Often it is not known if the hormone is working or not. The urine test can help clear up this question and contribute to a more efficacious treatment.

The other limitation of testing blood levels alone relates to the possible presence of a sluggish metabolism. In such a situation, blood levels may be higher or normal because of the retarded speed of processing within the system. It is in recognition of this reality that growing numbers of physicians are becoming educated to the fact that hypothyroidism may exist, and needs to be addressed, even though the thyroid blood level appears normal. Again, the urine test can help clarify this issue.

Jefferies suggests that mild degrees of cortisol deficiency may be due either to primary adrenal malfunction or secondary to inadequate stimulation by the pituitary or hypothalamus. One should mention the pioneering work of Selye who demonstrated that cortisol deficiency is a clear consequence of prolonged stress and contributes to some of the "diseases of civilization." (9)

The role of genetics is unknown. One can only speculate if an adrenal or cortisol defect could be passed on to offspring if, for example, both parents are affected.

If the imbalance becomes expressed in children, could perhaps the impact of deregulated IgA create widespread loss of critical immunity in mucous tissue throughout the body? The effect could possibly create any one or more of the following conditions: allergies, hayfever, asthma, food sensitivities, malabsorption, or digestive tract, bladder, kidney and lung problems. Testing for the imbalance and correcting the cortisol defect, if it exists, could perhaps circumvent the development of chronic health disorders in children. Among young girls, it might be easier to determine a damaging influence from adrenal estrogen at an age before ovarian estrogen is present.
With generations of animals, the author has seen an escalating severity of conditions related to this mechanism. Is there a parallel development among humans? Can we expect to see allergies and malabsorption in one generation, and when the defect is passed on to offspring, is there an increased potential for more serious conditions, such as autoimmune diseases and cancer?

These are all issues to be explored once the mechanism in humans has been identified.

CONCLUSION

The role of cortisol as an immune regulatory agent has been grossly neglected. An unknown, but probably very large, percentage of ill cats and dogs produce inadequate or bound cortisol as a result of contemporary breeding practices primarily, and, to a lesser degree, stress, aging, poor diet, and other environmental inputs. The cortisol defect opens a Pandora of biochemical events that produces elevated estrogen, bound thyroid hormone, and deregulation of major immune system cells. The author has treated many thousands of pets with a wide variety of otherwise intractable health problems by correcting this endocrine-immune abnormality with a hormone replacement program.

The program consists of physiologic doses of cortisone plus thyroid replacement in dogs, and cortisone alone in most cases for cats. Continued for the long-term over the course of an animal’s life, this approach effectively controls even severe diseases and contributes to health and longevity.

A test to determine the presence of the imbalance has been described, and can serve veterinarians as an important diagnostic tool for a potentially deadly yet overlooked cause of disease. The test also serves conscientious breeders to determine the health status of breeding stock and whether certain animals should be bred or not. The rationale here is that use of this test by breeders can help to reverse an alarming rise in genetically-based pathology that threatens the survival of domesticated canines and felines.

It is the author’s belief that a similar hormonal-immune sequence is a common, yet largely overlooked factor in human pathology and should be investigated. Jefferies has reported that physiologic dosages of cortisone can improve a number of human disorders involving an adrenocortical deficiency. His work has been largely overlooked. The experience with animals and the work of Jefferies and his followers strongly argues for exploring this area that may produce major diagnostic and treatment breakthroughs.

REFERENCES

1. Jefferies, W. McK. Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: A continuation of the cortisone story. Medical Hypotheses, 1994; 42; 183-189.

2. Plechner A. J., Shannon, M. Canine immune complex diseases. Modern Veterinary Practice, November 1976; 917.

3. Plechner A. J., Shannon M., Epstein A., Goldstein E., Howard E. B. Endocrine-immune surveillance. Pulse, June-July,1978.

4. Plechner A. J. Theory of endocrine-immune surveillance. California Veterinarian, January 1979; 12.

5. Plechner A. J. Preliminary observations on endocrine-associated immunodeficiencies in dogs - a clinician explores the relationship of immunodeficiencies to endocrinopathy. Modern Veterinary Practice, October 1979; 811.

6. Lemonick, M. D. A Terrible Beauty: An obsessive focus on show-ring looks is crippling, sometimes fatally, America’s purebred dogs. Time, December 12, 1994; 65.

7. Jefferies, op. cit., 185.

8. Jefferies, op. cit., 188.

9. Selye, H. Studies on adaptation. Endocrinology, 1937, 21; 169.

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