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This is a chapter from the book HYPOADRENOCORTICISM, copyrighted by the Adrenal Metabolic Research Society of the Hypoglycemia Foundation, Inc., 153 Pawling Avenue, Troy, New York, USA 12180. Upon the deaths of Dr. Tintera, M.D. in 1969, and later his wife, the Tintera's heirs passed all the collected papers of the Hypoglycemia Foundation, Inc. to the Hypoglycemia Association, Inc. (HAI) This has been reproduced here with the permission of HAI, Inc.

Endocrine Aspects of Ophthalmologic and

Otolaryngologic Allergy

Presented before the 27th Anniversary Program of the

AMERICAN SOCIETY OF OPHTHALMOLOGIC AND

OTOLARYNGOLOGIC ALLERGY

October 25-26, 1969 - Chicago, Illinois

Preparation of this paper has been supported by a grant from the Adrenal Metabolic Research Society of the Hypoglycemia Foundation, Inc.

SIDNEY SMITH (1771-1845): I am suffering from my old complaint, the hay fever (as it is called). My fear is, perishing by deliquescence: I melt away in nasal and lachrymal profluvia. My remedies are warm pediluvium, cathartics, topical application of watery solution of opium to eyes, ears, and the interior of the nostrils. The membrane is so irritable, that light, dust, contradiction, an absurd remark, the sight of a dissenter, - anything, sets me sneezing: and if I begin sneezing at twelve, I don't leave off till two o'clock, and am heard distinctly in Tauton, when the winds sets that way - a distance of six miles. Turn your mind to this little curse. If consumption is too powerful for physicians, at least they should not suffer themselves to be outwitted by such little upstart disorders as the hay fever.

Letter to Dr. Holland, June 1835.

Dr. Goldman, your President, asked me as an introductory speaker to pique your curiosity concerning many of the ophthalmological and rhino-otolaryngological conditions which relate to the whole man and his general chemistry. I feel that glaucoma, conjunctivitis, rhinitis, asthma, hay fever, Meniere's Disease, and chronic bronchitis are manifestations of a disturbance of the whole man rather than specific entities in themselves. They are signs of a basic chemical derangement which must be taken into consideration if treatment is to be effective. In my experience these manifestations occur in individuals who evidence adrenal cortical dysfunction. For the sake of this discussion, we will speak of these patients as being hypoadrenocortic. The primary objective in the treatment of hypoadrenocorticism is to achieve a state of homeostasis involving the endocrine glands, their dependent systems, and the organism as a whole. Homeostasis implies a balanced harmonious inter-relationship of the nutritional, endocrine, and nervous aspects of the organism. The therapeutic purpose, therefore, in endocrinology is to set up this state of balance and then maintain it.

This is a new era of diagnosis in which we are able to detect inborn errors of metabolism even at birth. Every chemical action in the body involves an inherited enzyme system which, in turn, is modulated by hormones. Tests are rapidly being developed which detect abnormal amounts of amino acids or other substances including incomplete steroids. Deficiency of an essential enzyme can also be exposed.

In the infant, eczema of the external auditory canal is not specific in itself. Bronchitis has a systemic basis. In a normal individual glaucoma does not occur as a separate disease. The pain of advanced, irreversible glaucoma is relieved by pilocarpine but it is more rational to relieve it by helping to restore homeostasis in the victim. Bronchitis has a systemic basis and may lead to asthma. Meniere's has proved to be a general physiological disturbance as many investigators have observed.

Adaption (or the lack of it) is an important factor in all physiologic or pathologic processes. Hence all maladies to some extent involve maladaption - failure to deal with stress. The ever increasing stress of civilization is a factor in many ophthalmological and otolaryngological conditions. IN this context, a nervous breakdown is the inability to adapt to nervous stress. In our treatment we do not employ tranquilizers or sedatives. As an adjunct to our program, we balance the autonomic nervous system with stabilizers, particularly Bellergal.

I am here to demonstrate that an ENT man treats more than specific conditions mentioned in the texts. I personally know that Dr. Goldman is a specialist interested in migraine, emotional disturbances, and other conditions such as anxiety neuroses, which seem far afield from his designated specialty. No one of you can claim that he treats only eyes, ears or noses.

At the present time Josephson is prescribing breathing and the good life; nevertheless, he was the first to demonstrate in 1935 that adrenocortical extract could relieve glaucoma.[2] Sam Roberts, the late Professor Emeritus of ENT at Kansas State School of Medicine, preached nutrition, and restoring the individual to as near normal health before attempting to correct a specific otolaryngologic condition.[3]

There has fortunately been a growing tendency to disregard the limitations of one's specialty and to visualize the clinical conditions as an end result dependent upon changes in physiology and body chemistry of the organs of an organism which is essentially one unified whole.

One of your members, Dr. William D. Currier,[4] in successfully treating a patient for Meniere's, was challenged by the internist to explain why he left his specialty to treat a mutual patient for rheumatoid arthritis which had heretofore been unresponsive to conventional therapy.

For the sake of credibility we have previously stated that about 16% of the population has some moderate-to-severe degree of hypoadrenocorticism with hypoglycemia but in actuality, the figure should read 67%, if all the arthritics, asthmatics and hay fever sufferers, alcoholics and other related groups are included. Indeed, no family, I believe, actually escapes the ravages of hypoglycemia resulting from stress induced hypoadrenocorticism. Even the coronary patient shortly after his attack will have a reactive hypoglycemia the severity of which depends on the adrenal response to stress. This reactive hypoglycemia may clear within a few months but it may persist and later be diagnosed as diabetes or latent diabetes. A sudden drop to hypoglycemic levels, it has been reported, may produce another coronary spasm and infarction.

We have observed many interesting physiological and psychological aspects of the hypoadrenocortic such as pinna ossificans which labels the patient Addisonian in many endocrinologists' minds. Only as recently as 1967, Henkin et al., of the National Institute of Health showed that patients with untreated adrenocortical insufficiency exhibit markedly increased detection sensitivity of taste and smell. In particular, they found that the auditory threshold return to normal after administration of adrenal cortical hormones and ACTH. Desoxycorticosterone decreased the serum potassium level but did not alter the auditory threshold.[5]

Neither the mechanism of the increased sensitivity to sound nor its locus of action in the nervous system is known but the phenomenon is not confined to the auditory system. All three sensory modalities investigated responded similarly to replacement with carbohydrate active steroids and in our cases, to ACE.

The olfactory sensitivity in adrenal insufficiency was found to be roughly 100,000 times (1 exp(3) - 1 exp(8) ) more acute than in normal subjects. Treatment with prednisolone returned the olfactory threshold to normal in the first day.[6]

In our cases, this sensitivity has been modified by allergic or vasomotor rhinitis, but with ACE, the extreme sensitivity which often causes nausea and vomiting, were quickly brought under control. Henkin and Solomon found an increased taste sensitivity to salt and many other substances in hypoadrenocortic patients as well as in hypopituitarism.[7]

The controlled testing was done by means of the electrogustometer and a lowered threshold was found in all of the hypoadrenocortic patients. Again, moderate doses of prednisone abolished this sensitivity in most of these patients in 1 to 3 days. The authors recommend that electrogustometry be used for diagnostic purposes in primary and secondary adrenal cortical insufficiency.

Allergy

In the course of treating several thousand patients for specifically an underlying glandular disorder, i.e., adrenocortical dysfunction, a sizable proportion of these patients presented myriad allergic symptoms. In the process of correcting the basic glandular dysfunction, it was early noted that when the general condition improved, the allergic manifestations either subsided, or entirely cleared up.

In reviewing the patients who presented themselves primarily with allergic complaints, it was found that in all of them many of the criteria were present essential for a diagnosis of hypoadrenocorticism relating to ophthalmologic, rhino-otolargyngologic conditions. Hypoadrenocorticism must be taken to imply a derangement of many hormones produced by the adrenal gland and not necessarily be thought of as under-function of the entire-gland. That is to say, that a disproportion exists among the three groups of adrenocortical steroids, namely, the glucosteroids, the mineralsteroids, and the 17-ketosteroids. Most of the patients fit into the picture of hypoadrenocorticism as previously described elsewhere. [8,15] But indeed, allergic patients have also been relieved whose diagnosis was adrenocortical hyperplasia, indicating an overactivity of one zone and a hypofunction of another. When the hypersecreting cells were inhibited through appropriate hormonal administration, a state of homeostatis was attained and symptoms alleviate. Carryer and Miller in a study of 101 patients with Cushing's Syndrome, secondary to adrenal tumor, or cortical hyperplasia, found two cases with a previous history of asthma and hay fever. Striking remissions occurred with the development of Cushing's Syndrome by recurred after surgical extirpation of a major portion of the functioning adrenal cortex. These men also suggest that defects in the metabolism of adrenal steroids, congenital or acquired, may be the basis for the so-called allergic diathesis.[16] It is a reasonable assumption that adrenocortical dysfunction provides the basis for all allergies but for practical purposes, we shall assume that there exists a state of hypofunction of the adrenal cortex involving the zona fasciculata and compromising carbohydrate metabolism whether the condition is inherited or subsequently induced by unusual stress.

Generally speaking, most allergies become manifest in their most severe form following a markedly stressful situation whether it be emotional or physical. Acute infections, including meningococcic meningitis, puerperal sepsis, and lobar pneumonia may be associated with necrosis of the adrenal cortical cells. The probably relationship between adrenal cortical damage and circulatory collapse in such diseases suggests the use of Eschatin.[17,61] In a review of the clinical uses of adrenal cortical hormones, references are made to a specific loss of the cortical factor in overwhelming infections as being important in shock associated with such conditions.

Perla and Marmorston [62] used cortical hormone as part of the treatment in severe infections including bronchopneumonia, therapeutic malaria and severe influenza. This plan of treatment resulted in maintence of normal blood pressure, decreased signs of toxicity, avoidance of circulatory collapse, maintence of appetite and shortening of convalescence.

When one or both parents are hypoadrenocortic with allergic manifestations, a child may be premature and shortly after birth show evidence of adrenal exhaustion such as electrolyte imbalance, projectile vomiting, eczema or severe diaper rash. An older individual may not have exhibited any allergic tendencies until subjected to surgery, emotional shock or other stressful situations.

Recently, a common more severe form of adrenocortical dysfunction is encountered in patients who have been treated with individual steroids for allergies or other unassociated conditions. It is quite obvious how cortisone or any of its derivatives may upset the intricate hormonal balance of the cortex by suppression of the zona fasiculata. On the other hand, the same may be said of ACTH, but this adrenocorticotropic hormone is specific for cortisone and to a lesser degree for the other cortical components and thus, the balance of total steroids should be used except in an acute emergency when a life-saving situation is presented and even then, larger doses of ACE will usually alleviate the condition without derangement of the normal balance.

The effects of cortisone, and hydrocortisone include neutrophilia, lymphopenia, eosinopenia, reticulocytosis, increased gastric secretion, inhibition of membrane permeability, decreased fibroblastic proliferation, alteration of immune reactions, alteration of central nervous system excitability and disturbance of melanin pigmentation.

Cortisone and hydrocortisone have important effects upon carbohydrate, protein, and fat metabolism. They cause decreased peripheral utilization of glucose and increased gluconeogenesis from protein. The explains the decreased tolerance to carbohydrates when excessive cortisone or hydrocortisone is administered.

Cortisone has been employed empirically for many symptoms common to hypoadrenocortical patients and as a consequence, the treatment of the allergic manifestations is further complicated since a state of homeostasis cannot be attained through the use of the whole adrenal cortex extract without great difficulty. Indeed, the only failures with ACE therapy have occurred after indiscriminate use of individual steroids has created an irreversible situation.

Our concept of disease has been materially augmented by Selye's exposition of his General Adaptation Syndrome. The allergic patient presents many of the manifestations described in the general adaptation syndrome including physical and laboratory findings as described by Selye. The allergic individual is one who is unable to respond to stress in a normal fashion.

John P. McGovern of Houston, President of the American College of Allergists, was quoted in the September 9, 1968 issue of "Medical Tribune." He said in part: "In many asthmatic patients, attacks repeatedly reoccur or become worse at night, generally between 11 p.m. and 4 a.m. a time coinciding with minimum excretions of urinary corticoids. These manifestations suggest that nocturnal physiological hypo-function of the adrenal gland certainly might be one of the factors favoring precipitation of an attack. Study of temporal relations between circadian as well as other cyclic control mechanism and recurrent allergic manifestations, such as asthma, might help provide a more satisfactory interpretation of certain of the allergic phenomena and thus perhaps lead to improved methods of treatment."

It has been indicated that the allergic state is one of the constitutional manifestations of "Hypoadrenocorticism" whether inherited or acquired. Rackmann followed a number of asthmatic patients for twenty to thirty years and found some to have two distinct episodes separated by a long symptom-free interval. The first episodes occurred in the teens or twenties and these he attributed to allergy or "extrinsic" causes, i.e. infections or other stressful situations. His interpretation is that the allergy and the infection are merely exciting causes which produce asthma in a patient who suffers from a definite constitutional disease and gives as one theory of explanation, a disturbance of adrenal function.[63]

In our large series of cases manifesting allergic symptoms, several findings have been constant with modifications, if in addition to the adrenal cortices, other glands are involved. The most important of these general findings may be enumerated as follows:

1. Relative lymphocytosis

2. Eosinophilia

3. Low, flat glucose tolerance curve or reactive hypoglycemia

4. Hypometabolism - low B.M.R. - normal P.B.I, T-3 and RaI uptake

5. Hyponatremia

Hypometabolism has generally been attributed to an atypical hypothyroidism since the B. M. R usually ranges from minus 10 to as low as minus 26, even though the P.B.I. is normal. Patients, although asthenic and exhibiting none of the classical symptoms of myxedema or thyroid dysfunction, were placed on thyroid medication and often responded with an exacerbation of their symptoms or showed marked sensitivity to the extract. On the other hand, minimal doses of proloid (1/4 gr.) stimulated the adrenal-thyroid axis with gratifying but not necessarily permanent results. If any improvement occurred, it could be explained an the basis of the response of the thyroid-adrenal axis. Within the past several years, the advocates of this thyroid hypometabolism were thrown into consternation when the now common P.B.I., T-3 and RaI determinations indicated normal thyroid levels.

Again, an explanation had to be forthcoming for the enterprising investigators who postulated that the fault lay at the "cellular level." Cytomel (tridiothyronine) was employed, again, with some success, in a few individuals, since in these particular cases, the thyroid-adrenal axis was, at least, partially intact. The failures naturally occurred in those individuals whose adrenals could not stand the further abuse of stimulation from the thyroid following the employment of the potent fractions of its hormone. The most that can be said for triodiothyronine, is that its action is rapid in onset and ceases suddenly when withdrawn. Desiccated thyroid is less expensive and equally effective if at all indicated but dosage should be in the range of 1/4 gr.

Returning to Selye's Adaptation Syndrome,[64] the criteria for adrenal insufficiency are the persistence of the thymus and a relative lymphocytosis. Most frequently, the allergic patient, unless experiencing an acute episode of an allergic reaction, shows a relative hymphocytosis and absolute eosinophilia.

Briefly, in 1936 Hans Selye demonstrated by a series of animal experiments that the organism responds in a "stereotypical" manner to a variety of widely different factors such as infections, intoxications, trauma, nervous strain, heat, cold, muscular fatigue, etc. The specific actions of all these agents are quite different. Their only common feature is that they place the body in a state of general or systemic stress. The infection initiating an asthmatic attack, or the contact with an allergen in the nasopharynx causing symptoms hay fever, or the chemical producing cutaneous reactions are all stressor agents.

During the stress reaction, all the organs of the body show involutional or degenerative changes while the adrenal cortex actually flourishes. This accounts for a normal or low normal value of steroid determinations when obtained in practice on allergic patients. We now are distinguishing between the effects of adrenal cortical insufficiency and adrenal cortical imbalance. It has been shown that groups of hormones from one of the zones may be normal while the others may be present in deficient or abundant concentrations. This is the alarm reaction or the first stage of the more prolonged general adaptation syndrome, which comprises three distinct stages:

In the General Adaptation Syndrome the most outstanding features of this stress response are: [64]

Experimentally it has been shown that thymico-lymphatic involution and typical blood count changes could be produced by adrenal cortical extracts even in the absence of the adrenals. Production of these hormones is therefore considered to be the indirect result of stress. ON the other hand, adrenal cortical extracts lessen shock and gastrointestinal changes and therefore these conditions are combated by an adequate adrenocortical response. Additionally, Selye showed in 1937 that the only procedure which could prevent an adrenocortical response to stress was hypophysectomy. Stress stimulates the adrenal cortex through the pituitary trophic hormones, or ACTH. Clinically, most allergic states have responded well to the adrenal cortical extract, individual steroids and ACTH.

Pottenger and Pottenger in 1938, were the first to report the effects of adrenal steroids in allergies using a crude adrenal cortical extract. The percentage improvement in intractable asthma was very high (85%). These findings were substantiated by other clinicians using the crude extract. Since the appearance of the purified extracts of Parke-Davis (Eschatin) and Upjohn (ACE), the literature is replete with beneficial results. [17, 61]

More recently, of course, the individual steroids, starting with cortisone and hydrocortisone and going on to the newer products, prednisone and prednisolone, and finally, hexamethasone, have proved to be effective in anaphylactic shock, status asthmaticus and other acute allergic conditions. However, these should not be used because of the severe side effects unless ACE proves to be ineffectual, which is unlikely. Even topical use on the eye has proved disastrous as indicated by several recent medical reports. These substances are used as replacement therapy in a sense, since the patient has to be given maintence doses. When medication is suspended the symptoms more often than not return and generally, in a more severe form. Thus, we may see a simple case of hay fever progress into fulminating asthma.

Our experience has been that previous steroid medication renders the patient much more difficult to treat successfully with adrenal cortical extract because the dosage of individual steroids necessary for a favorable response is above the physiologic level of what the adrenals normally produce. Hence, even though individual steroids are often miraculous in their immediate effect, aggravation of the underlying cause is precipitated if continued for any length of time. Prolonged use not only produces a further disfunction of the adrenal, but it very often leads to actual atrophy of the gland.

ACTH, likewise, my produce dramatic relief of symptoms but continued treatment, again, leads to an imbalance of three groups of steroids produced by the adrenals. In addition, ACTH is a protein and in allergic patients one always runs the risk of producing anaphylactic shock. ACTH is the specific tropic hormone for hydrocortisone which will be produced in larger amounts if the adrenal is capable of response. ACTH is not specific for the mineralosteroids (aldosterone) although there is some overlapping in the stimulatory effect of ACTH on the zona glomerulosa as evidence by the production of moon facies, increase in blood pressure, etc.

The 17-ketosteroids also are indirectly stimulated by ACTH but depend primarily on the gonadotropic hormones for their elaboration. It is readily foreseeable, therefore, that the employment of either individual steroids or ACTH will eventually cause a disruption of the balance of all of the adrenal cortical hormones.

Why then does ACE have a more beneficial effect than either cortisone or ACTH. Assume that there is a deficiency of glucocorticoids from the zona fasciculata. The stressor factor in this case is a pollen or other antigen which starts in motion the events enumerated for the general nervous system to produce adrenalin which, in turn, activates the hypothalmus which through humoral reactive hormones and nervous pathways to the pituitary causes the latter to secrete ACTH and other tropic hormones. Since the cells of the adrenal cortex which produce cortisone are deficient, there occurs a further imbalance with overproduction of mineralsteroids and 17-ketosteroids. The introduction of the whole adrenal cortical extract supplies a sufficient amount of the glucosteroids to bring their level to normal and thereby the body reacts physiologically in neutralizing the antigen through the release of antibodies from the lymphocytes and small white cells of the lymph. At the same time, if an overabundance of mineralosteroids is being produced, the introduction of aldosterone in the extract will lower the amount being produced through its feedback mechanism. Again, theoretically, if the adrenal production of 17-ketosteroids is subnormal or normal, the addition of another small amount is not going to produce any appreciable effect one way or the other, since it will have no effect upon the lymphocytes but will further assist in establishing normal balance.

In other words, the introduction of ACE tends to produce a state of homeostasis which is possible in no other conceivable manner. The intricacies and interactions of the 32 or more adrenal hormones are infinite since we know some are antagonistic and others synergistic with one another. There is an astronomical number of combinations necessary to catalyze the myriad enzymatic reactions which are going on constantly in order to maintain homeostasis in the whole organism. Variations in this process account for the differences exhibited by each patient and treatment must be modified accordingly.

French K. Hansel, in discussing respiratory allergy from the standpoint of the otolaryngologists, states that - "In the management of allergy of the respiratory tract, it is quite impossible to separate, for purposes of diagnosis and therapy, the upper from the lower types. Nasal allergy may exist alone or in association with bronchial asthma. Conversely, asthma rarely exists without some concomitant nasal involvement. When allergy affects al of the respiratory tract, the process must be considered as a whole and not as two separate units.[65]

Along these lines, I see patients with indications of hypoadrenocorticism such as undue fatigue, muscle pains, orthostatic hypotension, all relative to a fall in blood sugar, who at the same time present signs and symptoms of what has been diagnosed as sphenoid sinusitis, scintillating scotomata, nystagmus, and "eye aches." In the treatment of the underlying adrenal insufficiency, in addition to the restoration of normal physical activity, the glabellar headaches are relieved. The hyperactive pituitary in its attempt to stimulate the under-functioning adrenal, becomes hypertrophied or hyperplastic and cannot be contained within the confines of the sella turcica without pressure and resulting symptoms. Intravenous injections of 10 to 20 cc. of ACE relieve this situation by its feedback mechanism and the glabellar headaches (eye aches), nystagmus, and misdiagnosed sphenoid sinusitis disappear concomitantly. The severe migraine glabellar headache is often dramatically relieved by the parenteral injection of about 1,500 i.u. of gonadotropic or anterior pituitary like hormone derived from human placenta.

It is important to realize that the employment of ACE is not simply replacement therapy since discontinuation of this treatment does not result in the immediate return of symptoms. Adequate dosage of this extract will first of all supply a sufficient amount of lacking hormones to combat the stressful situation. At the same time, the feedback inhibition of the pituitary provides a four-hour refractory period in which the faltering cells may return to normal. When the pituitary inhibitory effect wears off these cells can function more efficiently usually for about a week at the beginning of treatment.

A very common condition presenting itself today, especially in women, is iatrogenic hyponatremia. Almost every pharmaceutical house has joined the campaign to eliminate NaCl through indiscriminate use of diuretics or "water pills." The possibility of hypokalemia or hyperkalemia is often mentioned but the critical wasting of sodium is overlooked and patients are placed on a low salt diet, with no regard to the physiological principles.

It is well known that hypoadrenocortics waste sodium, potassium and chlorides. We have devised an electrolyte clearance test which promises to be more definitive than any of the present day procedures for the detection of adrenal insufficiency. A twenty-four hour urinary excretion of the electrolytes is first determined, then the determination is repeated after a sodium chloride loading of 15 gm. So far, these tests show an astonishing above normal increase over the first twenty-four hour specimen. As a result of these observations, we have instituted, as a standard procedure, the administration of 10 to 20 gr. NaCl every day of the year, increasing to as much as 70 to 80 gr. on hot or humid days. There has been gratifying alleviation of the most common complaint, fatigue. For the allergic patient, salt tablets are far superior to any energizer yet devised. Data on this test are not complete, put preliminary evidence is most encouraging.

Treatment

These patients are in a state of negative nitrogen balance which is enhanced by the use of cortisone. Anabolic agents are therefore indicated. ACE is in itself anabolic. The most effective specific agent we have is "Durabolin." Mild secondary anemia is a frequent finding. B12 and B6 have been used because of the erythropoietic and adrenal saving effect. Usually the anisocytosis, poikilocytosis, and microcytic and macrocytic anemias are alleviated by ACE.

It is clear that adrenal hormones are able to forestall the alarming signs and symptoms of allergies but the mechanism is little understood. The high incidence of lymphocytosis in allergic states must have some significance. It was shown by Daugherry and White that the administration of ACE destroys the lymphocytes with the release of antibodies.[66]

In our experience scratch or patch-testing is only of academic interest and so-called desensitization shots seem to be of little or no value.

Androgens induce significant retention of calcium and potassium. In correlation to this a disproportionate amount of sodium is not retained. As a matter of fact, some patients increase the amount of sodium excreted. Therefore, to establish homeostasis even with a deficiency of anabolic hormones, the entire adrenal cortex spectrum must also be employed including aldosterone or DOCA to establish electrolyte balance.

Most of the anabolic steroids can cause hepatotoxic changes but when using them in conjunction with ACE we have never encountered difficulty on that score. (Fluoxymesterone (Halbestin - Upjohn) is roughly five times as anabolic and androgenic in its activity as methyltestosterone.) One gram daily of Ascorbic Acid in divided doses is recommended as the only oral vitamin supplement. The adrenal cortex reacts properly only in the presence of adequate Vitamin-C and cholesterol.

As we have seen in Selye's General Adaptation Syndrome, a normal response of the adrenals is necessary to avoid shock and other factors injurious to the organism. The release of the cortical hormones has an immediate action on the lymphocytic system. Almost invariably in allergies we find a relative lymphocytosis and eosinophilia but ACE reduces the lymphocyte count and many of the lymph nodes decrease in size or disappear. The lymphocytes, therefore, must be involved in this stressful situation. Although the role of the eosinophils is at present unclear the Thorn test is based on the fact that ACTH or epinephrine reduces the eosinophil count. A drop of 50% is said to be significant proof of adrenal insufficiency but this is not an entirely reliable indicator.

The standard explanation for many years regarding the allergic response is that symptoms of hay fever, asthma and eczema result from the contact of the allergen with the antibody. Much is left unexplained if one adheres to this idea. This antibody-antigen reaction is supposed to take place on the surface of the cell, injuring it and releasing histamine. This would indicate that treatment be directed toward preventing this reaction when in reality, the normal individual is constantly protected because of this reaction, since he has sufficient antibodies to neutralize the antigens constantly bombarding all tissues. True, there is a release of histamine in all allergic reactions. Our approach to the neutralization of this reaction is to use histamine azoprotein (Hapamine). Antibodies against histamine should alleviate the allergic state, but histamine acts as a haptin and is not antigenic in itself and must be coupled to a protein to form an antigenic complex. This was accomplished in 1943 by Gell[67] who was successful in coupling histamine to despeciated horse serum. Histamine azoprotein has been used to great advantage in effecting a quicker response to ACE in asthma, vasomotor or allergic rhinitis, physical allergy (heat, cold, light), gastrointestinal allergy, contact dermatitis, atrophic eczema, vertigo, periodic headache, liver extract sensitivity, and infantile eczema.

The allergic individual is one whose adrenals cannot meet the demands of the stressful antigens and reacts pathologically. Tissues react in a stereotyped manner to any antigen or injury and histamine is released for the protection of the organism as a whole. A chain of events follows: The vegetative nervous system reacts to the histamine and releases hormones from the adrenal medulla to stimulate the hypothalamus and pituitary which, in turn, causes the elaboration of the protective hormones from the adrenal cortex.

We have shown elsewhere that "hypoadrenocorticism" may be an inherited characteristic with typical physical findings, or normal adrenals may be injured to produce secondary manifestations. From the above precepts, the management of the allergic state would involve the prevention of further damage to the adrenals or assistance in the restoration of the malfunctioning adrenal cortical cells to normal. This is accomplished by giving adequate amounts of all the adrenal steroids in the form of an extract which also helps maintain a normal electrolyte level.

We know that all hypoadrenocortics have faulty carbohydrate metabolism as revealed by the glucose tolerance test which may show a low, flat curve or a reactive hypoglycemia. We also know all sugars and starches act as stressor agents.

Therefore, we consider the elimination of all readily available carbohydrates from the diet (high protein, moderate fat, minimal carbohydrate) more essential than local treatment and equally as important as supplying the needed steroids in their naturally occurring balanced concentration as found only in the extract.

The storage of carbohydrate is largely under adrenal control. Adrenalectomy decreases glycogen storage in the liver and muscles, while mineralocorticoids raise the glycogen concentration, especially in the liver. Adrenalin depletes the hepatic glycogen reserves, since it transforms glycogen into blood glucose. There is also a simultaneous diminution of muscle glycogen.

However, after a prolonged fast, and in other conditions, which cause depletion of hepatic glycogen stores, adrenalin may actually raise The liver glycogen. This is due to the fact that the lactic acid, formed by the hormone from muscle glycogen, is reconverted into hepatic glycogen through the "Cori Cycle." Thus, adrenaline transforms muscle glycogen into lactic acid and the latter is converted into hepatic glycogen, which, in turn, is broken down into blood glucose by the same hormone through the activation of specific enzymes.

The lactic acid content of the blood and muscles tends to diminish after adrenalectomy, apparently because of decreased lactic acid formation. On the other hand, adrenalin increases the lactic acid content of the blood due to the above mentioned conversion of muscle glycogen into lactic acid.

In susceptible individuals abnormal accumulation of lactate in the blood may produce muscular and emotional symptoms which we have observed for many years and were recently described by Pitts and McClure of St. Louis.[68] In cases where there is derangement of the glycogen-lactate-glucose cycle, a post prandial rise in blood sugar may result in an excess of blood lactate. This produces a state of anxiety - the "Non-neurotic Anxiety Neurosis." This is attended by fearfulness, feelings of impending doom, fear of going insane or fear of a heart attack. The physical symptoms attending such an episode include shortness of breath, chest discomfort, dissiness, faintness, shakiness, palpitations, and parathesias. Later, muscular aches may appear in the calves of the legs, the thighs, and temporal muscles. The last may present a challenge to the otolaryngologist. However, all the aches are markedly alleviated by intravenous injections of calcium preferably in the form of gluconate.

The temporal muscular involvement may be accompanied by a sensation of fullness in the ears. This latter phenomenon may also be produced by birth control pills as a result of the fluid retaining propensities of the progesterone as discussed at your last meeting in 1967.

On June 28, 1968, H.E.W. dispatched a bulletin on the adverse reactions observed in patients receiving oral contraceptives, citing a significant association in the development of thrombophlebitis and pulmonary embolism. An association was also implied, which has neither been confirmed nor refuted, with serious adverse reactions such as cerebrovascular accidents and neuro-ocular lesions, e.g. retinal thrombosis and optic neuritis. I have had patients who prior to my treatment reported many ocular and auricular symptoms particularly scintillating scotomata. When placed on oral contraceptives given in conjunction with ACE there have been no adverse side effects because the combination of steroids in the extract has the capability of correcting most hepatic conditions. The liver is then able to metabolize or detoxify both the estrogens and progestins and their precursors.

There are many EENT conditions dependent on the release of histamine and its subsequent involvement in tissue edema and interactions of antigens and antibodies. However, I will limit my discussion to only a few of the more salient conditions encountered most frequently, namely, glaucoma, Meniere's Syndrome, asthma, and glabellar headaches.

Glaucoma

In the course of consultations during the past several weeks with patients being treated primarily for hypoadrenocorticism, there have been at least a score who when first examined had some degree of glaucoma. In almost all cases, the condition has been arrested or in the earlier cases, appears to be progressing to a complete remission. I have not attempted to modify treatment prescribed by the ophthalmologist in any way. The improvement in the eyes is dependent upon the restoration of normal function of the total organism together with the focal assistance of the specialist, being cognizant, however, that the adrenal plays an important role in the recovery.

Dworetzky classifies the allergiec diseases of the eye anatomically.[69]

To this list, of course, we would add glaucoma.

ACTH and corticosteroids have assumed considerable attention but I am sure you are aware of the devastating side-effects, both systemic and topical from these agents. Both systemic administration of corticosteroids and their topical use in the eyes can cause serious, often irreversible, ophthalmic complications. These include exacerbation of Herpes Simplex Keratitis; also bacterial and fungal infections of the eyes, posterior subcapsular cataract, and glaucoma.

Josephson was the first to employ ACE in glaucoma with astonishing improvement in all cases.[2] He attributed the improvement to the normalization of the capillary permeability which eliminated edema of the ocular tissues. There is evidence that glaucoma represents an allergic state in which circulation through the canal of Schlemn is disrupted. Since all allergies, in my estimation, stem from adrenal cortical insufficiency it is logical to expect ACE to be beneficial. Josephson found that the administration of ACE caused a sharp drop in tension with a remarkable rise in visual acuity in primary simple glaucoma which had not responded to ordinary treatment. He stated that ACE offers a test of the secretory function of the eye as well as acting as a therapeutic agent of remarkable value. He was impressed by the promptness of response. Within 20 minutes after the administration of ACE the vision rose from 20/100 plus to 20/30 without correction in one of his cases.

Complete relief from pain and discomfort has generally been observed even in cases which have advanced to blindness. ACE therapy usually halts the drop in vision and reduces cupping of the disc. Injections of ACE (usually 10cc., i.v.) may be required as often as every 3 to 4 days but gradually the intervals are increased to once weekly, thence bi-weekly, etc. The patient usually has some other manifestation of allergic diathesis, i.e. hay fever, conjunctivitis or asthma.

Meniere's Syndrome

Bauer describes Meniere's Disease as characterized by recurrent attacks of sudden vertigo of the "special" type that passes off after several minutes or hours, sometimes days.[70] These attacks may be accompanied by temporary tinnitus and impaired hearing on the affected side. In severe cases, a widespread disturbance of the autonomic nervous system may occur with vomiting, abdominal pain or diarrhea. Anatomical studies revealed the commonly described "endolymphatic" hydrops without any signs of inflammation or hemorrhage. The similarity and combination of Meniere's attacks with migraine are highly suggestive of vasomotor origin. Intermittent labarinthic angioneurotic edema seems to fit best the underlying pathologic process. Vasomotor imbalance, specific allergy or a chronic disease of the inner ear are often identified as inciting factors in these patients. Vasoconstricting or vaso-dilating drugs are capable of producing an attack; therefore, Bellergal with its ability to neutralize both propensities is a vital component of the overall regimen recommended for autonomic nervous system instability together with the rest of the regimen employed for any allergic condition.

In our experience, Meniere's Syndrome is found only in patients evidencing an underlying adrenal cortical insufficiency. Therefore, our approach to diagnosis and treatment lies in the area of allergy. The texts say that acute symptoms of Meniere's can be brought on by infections and emotional distress. On this premise alone, one can readily see the connection with hypoadrenocorticism. Stress, from whatever source, evokes acute symptoms of the various systems including that of the ear.

Our approach to Meniere's emphasizes evaluation of the carbohydrate metabolism; study of salt and potassium handling via the electrolyte clearance test; careful search of the patient's history for other allergic manifestations such as eczema, hay fever and the like, and for recent infections or emotional stress.

Treatment consists of elimination of readily absorbed carbohydrates, increase of salt in the diet (including extra salt in tablet form), frequent small feedings, and Eschatin (Adrenal Cortical Extract) 10 cc. on a once a week schedule. Desensitization should be limited simply to injections of histamine azoprotein, in very small doses initially and gradually increasing to one cc.

As we feel, Meniere's along with other problems, falls into the group of symptoms of adrenal cortical insufficiency, treatment of the existing adrenal cortical pathology effects relief of symptoms and usually eliminates the entire syndrome.

We are well aware that the texts suggest the elimination of salt because of its "fluid retaining property". However, these patients are in a state of negative nitrogen balance and require salt for proper metabolism of protein, and also, the adrenal cortical insufficiency involves failure of the zona glomerulosa in handling sodium and excessive amounts are lost in the urine and perspiration. Increasing salt in these patients improves the sodium-potassium balance and decreases the production of aldosterone.

It is generally accepted that allergic problems are aggravated by stress from whatever source, be it physical or emotional. This implicates the adrenal cortex. In a previous paper, "The Hypoadrenocortical State and Its Management," 1955, we categorized the hypoadrenocortic according to symptoms. Dizziness and an uncomfortable feeling in the head are noted in a very large percentage of the patients. Treatment as described eliminates these complaints. We should like to point out also that in patients who show a slightly elevated blood pressure with Meniere's it is our conclusion that this elevation usually indicates a compensatory action of the zona glomerulosa resulting from excessive stimulation from the pituitary because of the failure of the zona fasciculata. Again, treatment of the adrenal cortical insufficiency effects a reduction in blood pressure without the use of anti-hypertensive drugs and withdrawal of salt. The anti-hypoglycemic diet with the Eschatin acts to regulate the entire adrenal cortical function, suppressing the overactivity of the zona glomerulosa and increasing the efficiency of the zona fasciculata and zona reticularis.

Meniere's Syndrome then falls into the picture of adrenal cortical insufficiency and is relieved permanently by adherence to the anti-hypoglycemia diet, use of salt, and periodic injections of adrenal cortex extract plus any other hormonal djuvant indicated by deficiency in a target organ. The intricacies of the hydrops of the vestibular system together with modifications of treatment - hormonal, dietetic and nervous stabilization - have been amply described by Dr. Goldman in several articles, the most recent and detailed of which appeared in 1965.[71]

Asthma, hay fever, and many of the allergic dermatitides are treated in like manner and respond even after the outmoded desensitization therapy had failed provided the patient has not been thrown completely out of balance by previous therapy with individual steroids.

Summary

Our clinical experience and Selye's fundamental research lead us to the conclusion that a very large number of pathological conditions become apparent only when bodily defense is "derailed" because the adrenal cortex is exhausted by excessive stress or the adrenal cortex is inherently deficient. These conditions can be forestalled or alleviated through supporting and resting the cortex and reducing internal and external stress. This can be accomplished with diet and ACE and by stabilizing the autonomic nervous system and controlling any associated endocrine dyscrasia.

References

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9. Goldman, Herbert B., M.D. and Tintera, John W., M.D.: HYPOADRENOCORTICISM IN OTOLARYNGOLOGY:, A.M.A. Archives of Otolaryngology, Vol. 64, pp.381-389, November 1956.

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