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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 Schizophrenia:

Hypoglycemia of Hypoadrenocorticism

Journal of Schizophrenia

Vol. 1, No. 3, 1967

John W. Tintera, M.D.

30 South Broadway

Yonkers, New York

The preparation of this paper has been aided by a grant from the Hypoglycemia Foundation, P.O. Box 444, Scarsdale, New York.

A growing body of data lends strength to the conviction that schizophrenia can no longer be considered a purely mental disease. Like alcoholism, schizophrenia must be approached with the whole human organism in mind. This attitude was proposed more than forty years ago by Meyer (1948). Our mission is to coordinate and harmonize the "psyche" and the "soma" through the principles of genetics, biochemistry, enzymology and especially endocrinology. This can be no surprise even to the psychoanalyst. Over two thousand years ago the ancients described the pineal gland as the seat of the soul and in the seventeenth century Descartes agreed with them (Harvard, 1891). Freud himself was speaking of endocrinology when he said, "These mental disturbances are open to therapeutic influence only when they can be identified as secondary effects of some organic disease (Freud, 1943).

In recent years psychiatry has come to sense some limitation as a descriptive science. Mere manipulation of the psyche left something to be desired. Other disciplines were invoked. Surgery seemed too brutal. Convulsive therapy was helpful as a last resort. The success of Hoffer (1957) with nicotinic acid and diet is a promising step. The steady increase in mental hospital population is the U.S. reversed itself abruptly in 1955 with the advent of tranquilizers and antidepressants. By 1963 the mental hospital census in the U.S. was 135,000 less than had been projected (Simpson, 1966). Although they may have been spared hospitalization, the picture of 135,000 numbed and somewhat toxic and sometimes addicted citizens is not entirely a satisfactory one to contemplate.

Endocrine Aspects of Schizophrenia

Studies attempting to correlate psychotic states with adrenal function are well known. (Bunny et al, 1965a; Bunny et al. 1965b; Suwa et al. 1962; Curtis et al. 1960; Persky et al. 1959). Other investigators (Simon & Gillies, 1954; Larsen, 1964) tried to associate mental aberration with such physical attributes as bone and muscle measurements, fat distribution and blood pressure, all of which may certainly carry endocrine connotations.

My firm belief in the vital importance of the endocrine system in pathological mentation was sparked in the early forties when I first insisted on 3-4 hour glucose tolerance tests. The laboratories apologized for seemingly incorrect readings although they had double-checked their techniques. What mystified them was the low flat curves derived from disturbed early adolescents. This laboratory procedure had been previously carried out only for patients with physical findings presumptive of diabetes.

Dorland's definition of schizophrenia (Bleuler's Dementia Praecox) includes the phrase, "often recognized during or shortly after adolescence", and further, in reference to hebephrenia and catatonia, "coming on soon after the onset of puberty."

These conditions might seem to arise or become aggravated at puberty, but probing into the patient's past will frequently reveal indications which were present at birth, and during the first year of life, and through the pre-school and grammar school years. Each of these periods has its own characteristic clinical picture. The picture becomes more marked at pubescence and often causes school officials to complain of juvenile delinquency or underachievement. A glucose tolerance test at any of these periods could alert parents and physicians and could save innumerable hours and small fortunes spent in looking into the child's psyche and home environment for maladjustments of questionable significance in the emotional development of the average child. The negativism, hyperactivity, and obstinate resentment of discipline are absolute indications for at least the minimum laboratory tests: urinalysis, complete blood count, P.B.I. determination and the 5-hour glucose tolerance test. A glucose tolerance test can be performed in a young child by the micro-method without undue trauma to the patient. As a matter of fact, I have been urging that these four tests be routine for all patients, even before a history or physical examination is undertaken.

In almost all discussions on drug addiction, alcoholism, and schizophrenia, it is claimed that there is no definite constitutional type that falls prey to these afflictions. Almost universally the statement is made that all of these individuals are emotionally immature. It has been our goal to persuade every physician whether he is oriented toward psychiatry, genetics or physiology to recognize that one type of endocrine individual is involved in the majority of these cases - the hypoadrenocortic. In most instances he has an inborn error of metabolism, with failure in the production of certain adrenal cortical hormones which initiate and control the interaction, activation, and inhibition of certain enzymes. Alcohol dehydrogenase, for example, has definitely been incriminated in the alcoholic and the barbiturate addict. In the schizophrenic, time and again various peculiar metabolites have been shown to be related to carbohydrate intake and reflect a breakdown in the cycle in which the cerebral cortex activates the vegetative nervous system which in turn stimulates the productions of catecholamines necessary to mediate the hypothalamic-adrenohypophiseal-adrenocortical complex (Kaplan, Inf. Comm.).

Hypoadrenocortical Syndrome

I first described the hypoadrenocortical syndrome in 1949 (Tintera & Lovell, 1949) in connection with alcoholism and later, in 1955 (Tintera, 1955) summarized the typical findings in 200 selected cases. The chief complaint were as follows:

Other findings according to organic systems are listed with their frequencies in these papers. It is germane, however, to give here the chief physical and laboratory findings.

We need not, and indeed should not, limit our consideration to the first manifestation of schizophrenia in the pubescent child since even at birth such ominous stigmata may be present as hyponatremia, hypoglycemia, hypomyotonia, and hyperreflexia. The frequently premature offspring of parents who exhibit allergies or other hypoadrenocortic indicia may have gastric symptoms such as projectile vomiting or pylorospasm, often severe enough to be fatal. Later we see the hyperactive preschool child and the underachiever in grade school. His chief scholastic barrier is the inability to concentrate on mathematics, and finally he fails algebra and/or geometry. Then there is the negative adolescent with failure in development of secondary sex characteristics.

In typical sequence the colicky newborn develops diaper rash followed by frank eczema. Later (after T. & A.), hay fever often arises which may eventually lead to asthma (post-appendectomy) and finally schizophrenia intervenes, at which time the allergies disappear. Incidentally, the post-appendectomy asthma is an argument for the reticuloendothelial function of the appendix. mesenteric adenitis mimics appendicitis; 85% of the removed appendices are innocent.

Improvement in the schizophrenic is usually attended by a return of asthma. We have demonstrated elsewhere that hypoadrenocorticism is the basis of the allergic response (Blaine, 1965). Stress may activate the hypothalamus-pituitary-adrenal axis to such an extent that sufficient steroids are elaborated to control the allergy but at the same time the balance is disturbed since ACTH is specific for glucocorticoids, but not for mineralocorticoids and 17-ketosteroids to an equal degree. For this reason it is illogical to prescribe individual steroids such as cortisone or cortisol without regard to the synergistic and antagonistic hormonal relationship.

The endocrinologist is not mystified by the striking clinical improvement in many psychiatric patients following electro-convulsive therapy. In addition to interrupting the mental processes, this electrical insult to the organism stimulates the adrenal cortex to pour out tremendous quantities of properly proportioned corticosteroids (Graham & Cleghorn, 1951). This is beneficial if the adrenal is able to respond but when the adrenal is already exhausted, the result may be disappointing. E.S.T. has a definite place in the psychiatric armamentarium provided the patient has been conditioned previously with A.C.E. (adrenal cortex extract) but not with individual steroids which only create imbalance among the 32 or more steroids involved. Employing these principles of pre-treatment with A.C.E., Connason and Ryberg (1957) obtained remarkable results, even in long-standing cases. In their series, the milder foreign protein stimulus was used instead of electroshock.

Carbohydrate Metabolism

The only definitive gauge of impaired carbohydrate metabolism in the schizophrenic and/or hypoadrenocortic is the five-hour glucose tolerance test. In young individuals with hypoadrenocorticism or pituitary-adrenal insufficiency, a low, flat curve is observed. This moderate hypoglycemia induces a craving for carbohydrates, alcohol, or drugs which afford temporary relief of symptoms such as nervousness and feelings of unreality. Hepatic damage results from prolonged abuse of these agents. Fatty infiltration follows glycogen depletion and the GTT curve then will be characterized by a sudden initial rise to a high plateau followed by and abrupt drop, technically reactive hypoglycemia. In the pituitary-adrenocortic with obesity the rise reaches hyperglycemic levels and eventually declines to hypoglycemic values. Without dietary indiscretions, the curve may remain flat until the climacteric when again a further disturbance in the steroid balance may arise as a result of gonadal failure. The adrenal produces 65% of the male hormone in the man but only 15% of the female hormone in the woman during the child-bearing years. The absolute shutdown of the gonads puts a greater load on the already deficient adrenals and many acute episodes are encountered at this age, especially in the female when the adrenals are required to produce 100% of the estrogens.

Cortisone, or its derivatives, is not the answer to adrenal deficiency, as evidenced by a 13 year old girl who developed chronic nephrosis with marked edema. Hospitalized at one of our local university medical centers, she was given the generally approved dose of 60 mg. prednisone to which she did not respond. The dose was doubled to 120 mg., then to 240 and finally to 320 mg. per day, at which point this shy, unobtrusive child became a manic schizoid, destroying so much hospital

Figure 1 Glucose tolerance curve of 13 year old patient

equipment she had to be restrained. The 4+ proteinuria persisted and she, along with seven other children were considered failures on prednisone and as a last resort, an untried experimental drug was proposed, whereupon the protesting parents sought other advice.

When I first saw her, the urine boiled solid in the test tube. The day after the initial dose of Eschatin the urine was absolutely clear. She made a stormy but complete ambulatory recovery with A.C.E., diet, etc. The GTT showed a sever diabetic curve. After recovery, a normal curve was obtained, except for an exceptionally low fasting level, shown in Figure 1. What was the cause of schizophrenia in this case? Evidently, it was a derangement of cerebral carbohydrate metabolism. During intensive A.C.E. treatment, she was a good student, but now on maintenance does not concentrate as well, failing most subjects, notably algebra, but she is alive.

Case Histories

The following case histories represent patient, who on the average had previously been treated by 10 physicians and 2 psychiatrists. All demonstrated moderate to severe emotional disturbances but no specific psychiatric diagnosis is offered:

Case 1

Patient: T.H. First seen 6/5/62; Age 35; White female. Always tired, born tired. Quite upset, cries for no reason. Difficulty in concentrating. Good marks in school but had to study lying down. On and off thyroid (Proloid) for 12 years. 2 children (never felt better than when pregnant. Put on Dexedrine 1960, followed by hypoglycemia collapse Feb. 1960. On low-carbohydrate diet for 4 months, then returned to regular diet. Same year spent 6 weeks in psychiatric hospital for overdose of Librium where the diagnosis was made of anxiety, neurocirculatory asthenia. Still on amphetamines. Saw 12 MDs in past year. Blood pressure has been 80/40. Craves sweets. Gets rose fever and vasomotor rhinitis. Adores pickles.

PE.: Long index fingers, hypoadrenocortical teeth, positive Rogoff.

Fig.2 Glucose tolerance curve for Case 1

GTT: 1960: F-81, 1/2-136, 1-167, 2-133, 3-108, 3 1/2-123, 4-91, 4 1/2-95, 5-87. P.B.I.-11.8mcg%.

Diagnosis: Hypoadrenocorticism, hypo-ovarianism (mild), autonomic nervous system instability, orthostatic hypotension.

RX: AdrenalCortical Extract (A.C.E.) B6, B12, Theelin, Durabolin, Belergal.

Course: Short periods of slight improvement through 7/28/62. Patient not faithful to diet at first and continued to take tranquilizers, but by 10/16/62 patient stated enthusiastically that she was functioning one more as a human being. Discharged to family physician. Admitted to hospital 8/1/64 with acute pyelitis, discharged 8/6/64. Admitted to hospital 1/29/65 with diagnosis of neurotic depression and conversion hysteria; discharged 2/7/65. Admitted to hospital 4/13/66 in a hypoglycemia collapse, at which time the glucose tolerance test was F-60, 1/2112, 1-127, 1-94, 3-56, 4-48, 5-46. Discharged 4/20/66. 11/23/66 - First consultation since 10/26/62. In and out of hospital four times. Had not been following diet. Taking Eskatrol twice a day. Patient returned to hypoglycemic regimen. 11/28/66 - "felt like a zombie." Crying, depressed, can't concentrate. 12/13/66 - Patient is beginning to have periods of "feeling decent" but can be thrown into panic by being forced to make a "decision." Referred back again to family physician in a manageable state.

Case 2

Patient: H.J. First seen 4/14/58; Age 21, White female. Fears and anxiety (worse in crowds). Afraid to leave her house. Dizzy spells. Saw psychiatrist 2-3 times a week for 3 years. Was "afraid" of him. Had ambulatory shock treatment Oct. 1956 (3 electroshock -5 insulin). Received increasing doses of Sodium amytal each visit - couldn't talk otherwise. Less nervous driving car; short periods of employment. Took tranquilizers - also Dexamyl. Perspires profusely; started to gain weight at 5 or 6. Always a tom boy. Used depilatory last 3-4 years upper lip. chin, side of face. Menstrual difficulties. No sex activities. Sighing respiration. Trochanteric obesity at 12 or 13. Candy binges.

Fig 3  Glucose tolerance curves for Case 2

P.E.: Unremarkable, except for separation of upper incisors, high palatal arch, mild hirsutism, long index fingers, 3-4 interspace tenderness, positive Rogoff. Blood pressure 152/90. Ht. 5'5". Wt 135.

GTT: April 1958: F-90, 1/2-116, 1-86, 2-96, 3-80, 4-82.

Diagnosis: Mild hypopituitarism with secondary hypo-ovarianism and hypoadrenocorticism.

RX: Diet, A.C.E. Benadryl. Theelin, B6, B12, Bellergal, Menagen, Norlutin.

Course: Very slow improvement with gradula increase in activities outside the home. Employment status also improved. Many periods when symptoms returned - shaking, anxiety, panic, depression but by 11/2 years was married and moved to Wyoming. Works steadily and reports good general condition. Blood pressure normal. Death of 18-month old baby 1966 brought on period of "exhaustion". Determines own need for A.C.E. 5-10 cc per month. Leads comparatively extravertive life even withstanding the collapse of her dream to run dude ranch.

Case 3

Patient: P.M. First seen 4/4/47; Age 32; White female. Depressed, confused, irritable. Tired and too weak to stand. Migraine since age 17, mild allergies. Fingers blanch with mild cold. Vague fears for self. Cries often, "impossible to live with."

P.E.: Wt. 105, Ht. 65", blood pressure 136/82, positive Rogoff (rt), dermographia.
Fig.4. Glucose tolerance curve for Case 3

Diagnosis: Hypoadrenocorticism, hypo-ovarianism.

RX: Diet, A.C.E, Theelin, Gynergin, Hepthis, Cortate Pettets-DOCA, Proloid, Presidon, Bellergal.

Course: Slow recidivous progress as activity increased. Much improved with gain in weight. Patient not seen between Dec. 1956 and Jan 28, 1964, during which period she had required psychiatric hospitalization. Now in a stormy menopause. Rogoff strongly positive. Slow progress again. Course of shock treatments recommended 7/65. Tranquilizers and also Bellegral, diet, A.C.E. (increased doses), Theelin, Valium, B6, B12, Norlutate, Menagen. Within a month shopped. Now back at work and coping with unusual stress.

GTT: Jan 30, 1964: F-90, 1/2-137, 11/2-98, 2 1/2-78, 3 1/2-65, 4 1/2-79, 5 1/2-79

Case 4

Patient: L.R. First seen 11/20/61 - Age 11.5 White female. Tired, no energy, allergies. Can't concentrate, gets dizzy in math class. Colic and projectile vomiting as an infant. Intense early family trauma. High I.Q. Under psychiatric care. An emotionally disturbed child. Difficult to manage.

Fig. 5, Glucose tolerance curve for Case 4

P.E.: Wt. 77, Ht. 54", blood pressure 110/70, allergic conjunctivitis, Vasomotor Rhinitis, mod. positive Rogoff, P.B.I 5.3mcg%

GTT: 11/1/61; F-110, 1/2-188, 1-183, 2-150, 3-112, 4-110, 5-102.

Diagnosis: Mod. hypoadrenocorticism, sexogen insufficiency, "emotional disturbance."

RX: Diet, Lipo, A.C.E., Bellergal, API., Theelin, B6, B12, Will need Proloid and progesterone.

Course: Steady dramatic improvement in school work, family relationships, life interests and energy output. Discharged 10/64 and regular regimen stopped and invented own diet. Menarche marked by irregularity at age 15. Day of repeat Glucose Tolerance Test Oct. 1966 made a tentative attempt to slash wrists and was hospitalized and given intensive endocrine therapy with prompt favorable response. Outside school privileges as in-patient.

GTT: Sept. 1966: F-80, 1-224, 2-240, 3-191, 4-95, 5-42, 6-74.

Oct. 1966: F-80, 1/2-180, 1-230, 2-148, 3-130, 4-55, 5-67.

Case 5

Patient: P.H. First seen 12/11/63; Age 37; White female. Depression, agitation, tiredness since childhood. Life seemed bleak, lived from day to day. Saw endocrinologist in 1961 for weight when she was told her Glucose Tolerance Test was normal. (In 1957 it had been: F-88, 1/2-83, 1-87, 2-80, 3-71.7, 4-57). Has temper tantrums and screams at her 3 children. No interest in sweets but likes pickles and pickle juice. Tried suicide by sleeping pills 9 years ago. Intermittent treatment by psychiatrist. Has two siblings, one in mental hospital, other has "nervous stomach"

Fig 6. Glucose tolerance curve for Case 5

P.E.: Wt 130, Ht. 5'1", blood pressure 120/62. Hyperactive reflexes, mild girdle and lower trochanteric obesity, mild hirsutism, 4th interspace tenderness. P.B.I. - 3 mcg%.

Diagnosis: Mild hypopituitarism, hypoadrenocorticism, hypo-ovarianism and hypothyroidism.

RX: Diet, Bellergal, Menagen, Proloid, Theelin, A.C.E, B6, B12. Later Durbolin, Norpramin.

Course: At first patient did not stay on diet and progress was very slow. In 9 months felt very well and engaged in wide variety of activities. Depression and fatigue followed series of serious stress situations but is now enjoying life.

GTT: Oct 12, 1966: Afternoon GTT: F-105, 1/2-175, 1-206, 2-108, 3-88, 4-101, 5-95

Case 6

Patient: K.B. First seen 6/23/59; Age 44; White female. Depression at the smallest challenge; unable to handle decisions, cries for no reason; so self-confidence; no interest in anyone or anything. Very attached to mother. Hospitalized at 6 for overactive thyroid. Father died April 1948; 3 electroshock treatment at this time. Balked in panic twice at approaching matrimony. Married Dec. 1948. Three children. Well during pregnancy, depressed post-partum. Minimal sexual pleasure. Wanted whole family to live with mother. Intolerable alcoholic husband.

Fig. 7, Glucose tolerance curve for Case 8

P.E.: Wt 131, Ht. 65", blood pressure 152/85. Crowded lower incisors, long index fingers, exaggerated reflexes, such trochanteric obesity, 4th interspace tenderness, P.B.I - 6.8 mcg%.

GTT: F-90, 1/2-139, 1 1/2-117, 2 1/2-71, 3 1/2-67, 4 1/2-59.

Diagnosis: Hypoadrenocorticism, hypo-ovarianism, autonomic nervous system instability

RX: Bellergal, Menagen, A.C.E. Theelin, Testosterone, Benadryl, B6, B12, Durabolin, Deprol, Valium, Heparin and diet.

Course: Very slow undulant progress. Constant severe marital aggravation. Took handful of Bellergal and Phenobarbital Feb. 1960. 4 electroshock treatments April 1963. Very slow progress since then, not always diet-faithful. Still "up and down" but excursions less wide, anxieties less specific and able to work quite steadily. Still living under extreme uxorial stress. Blood pressure drops with sense of well-being. Working steadily with increased ambition. Highest Civil Service rating.

Case 7

Patient: H.M. First seen 11/7/56; Age 23; White female. Nervous-crying spells. Felt like an outcast at school. "Nervous breakdown" at 15. Thought her food was poisoned. Shock treatments. Closely attached to mother. Eggs made her vomit. Married two years. Baby eight months old. Cried all the time after baby was born. Didn't nurse it - afraid her breast would sag. Afraid her mother would hurt the baby. Had shock treatment again. Depressed. Cries. Can't sleep. Irrational with nembutal. Cowered in corner at sight of sphygmomanometer. "I don't want any more shock treatments."

P.E. Wt. 106, Ht. 62", blood pressure 132/90. Swollen turbinates, long right index finger, adrenal teeth. positive Rogoff, exaggerated reflexes.

GTT: F-100, 1/2 180, 1-155, 2-110, 3-95, 4-75.

Diagnosis: Hypoadrenocorticism, hypo-ovarianism (mild)

RX: Diet, A.C.E., Benadryl, B6, B12, Theelin, Bellergal, Noludar.

Course: Dramatic improvement with first treatment. Uneventful normal delivery 2/29/60. Felt well afterwards. Nursed the baby. Discharged. Felt very well during next pregnancy but went into severe post-partum depression 6/27/61. Recovered at once with A.C.E. and is feeling very well.

Case 8

Patient: D.H. First seen 3/13/61; Age 44; White female. Year ago felt she was losing her mind and has not felt right since. Was afraid she would strike people - would have to leave any social situation in panic; couldn't look in a mirror, couldn't face strangers; couldn't take a bath; afraid of harming children. Saw 3 psychiatrists - told cure would take 3 years. Taking Librium.

P.E. Wt. 133. Ht. 65", blood pressure 100/70. Crowding of lower incisors, 4th interspace tenderness, liver enlarged and tender. P.B. I. - 5.1 mcg%.

Diagnosis: Hypoadrenocorticism, hypo-ovarianism.

RX: Librium, A.C.E., Theelin, B6, B12, Bellergal, Menagen.

Course: Progressed slowly, by 2 months was having more good days than bad. Good periods lengthened slowly. Specific phobias lessened greatly. Patient now performing quite normally with occasional bouts of fearfulness under severe stress situations, as when unwed daughter became pregnant.

GTT: 2/2/61; F-92, 1/2-135, 1 1/2-94, 2 1/2-87, 3 1/2-70, 4 1/2-84.

Case 9

Patient: T.L. First seen 5/10/66; Age 31; White female. Nervous breakdown, disturbed anxiety, depression for one year. (Diagnosed by psychiatrist - schizophrenia with paranoid tendencies.) Tofranil made her worst. Also had hepatitis. Thinks often of suicide.

Fig. 10, Glucose tolerance curves for Case 9

P.E.: Weight 120, Ht. 64", blood pressure 110/70, conjunctivitis, spots of pigmentation on neck, long index fingers, Rogoff tenderness, exaggerated reflexes. P.B.I. - 4.8 mcg%

GTT: 2/6/66; F-88, 1/2-153, 1-135, 2-78, 3-78, 4-65, 5-68, 6-85.

7/62 post-hepatitis: F-124, 1/2-200, 2-202, 3-120, 4-120. (hepatic curve)

Diagnosis: Hypoadrenocorticism

RX: A.C.E., B6, B12, Estrogens.

Course: Gradual definite improvement in mood. Increased energy and complete absence of all original complaints as of 12/66.

Case 10

Patient: C.S. First seen 9/25/62; Age 42; White female. Referred with diagnosis of hypoglycemia. Nervous, doesn't sleep. Deep sense of inadequacy, afraid of losing her job. (even when employer promotes her and pays her more). No energy. Ten years ago had a "nervous breakdown" described as paranoid schizophrenia. Recent consulting psychiatrist thinks psychotic exacerbation possible. Gets rose fever. Already on hypoglycemia diet and tranquilizers.

Fig. 11, Glucose tolerance curves for Case 10

P.E. Wt.136, Ht. 63", blood pressure 110/70, P.B.I. - 6.2 mcg%. Swollen tubinates, sl. crowding lower incisors, long index fingers, moderate trochanteric obesity.

GTT: F-96; 1/2-159, 1-135, 2-136, 3-125, 4-77, 5-97.

Diagnosis: Hypoadrenocorticism, Mild hypo-ovarianism.

RX: Decreased tranquilizers, A.C.E., Menagen, Bellergal, B6, B12, Durabolin, Theelin.

Course: General improvement was rapid. Emotional state and energy output goo. Fear of losing job and sense of inadequacy in that respect kept returning in various degrees. Had 7 electroshock treatments in July 1963. The "job fixation" has been reduced and other wise the patient feels very well.

GTT: 8/3/65; F-111, 1/2-125, 1-108, 2-92, 3-108, 4-108, 5-92.

Case 11

Patient: S.B. First seen 10/22/58; Age 33; White female. Eczema at five. Asthma since six-severest with first pregnancy. Recently every morning. Always controlled with Tedral and Phenobrab. Food allergies during emotional upheavals. Depressed, nervous, snaps at people. Pain in her chin since adolescence - worse with nervous spells. Chews her lips until they are sore. Had a short "nervous breakdown" - screaming nude in the street, thought husband wanted to kill her. Had psychotherapy but no shock treatment. Has no feeling for her 10 year old son "effeminate."

Fig. 12, Glucose tolerance curves for Case 11

P.E.: Wt. 133, Ht. 65", blood pressure 118/72. Allergic rhinitis, adrenocortical teeth, high narrow palatial arch, 4th interspace tenderness, pos. Rogoff on rt., exaggerated reflexes. Mod. trochanteric obesity.

Diagnosis: Hypoadrenocorticism, hypo-ovarianism.

GTT: F-89, 1/2 -123, 1-92, 3-98, 4-54.

RX: Diet, A.C.E. Benadryl, Bellergal, Menagen, B6, Theelin, Norlutin, Diuril, Aldactone.

Course: Rapid improvement until wheezing attacks became rare. Two or three acute hypoglycemic episodes with severe schizoid manifestation associated with diet lapses. Dramatic instantaneous recovery during intravenous injections of Eschatin by family physician. Great improvement in mood. Activities extended to include water skiing and travel to Europe. Has gone through hay fever seasons without any asthma.

Case 12

Patient: L.C. First seen 6/20/62; Age 11; White female. Bright fidgety and nervous, inattentive in school. Gaining weight. Steals money and useless trinkets, mostly from family. Impossible to reason with. Was thumb-sucker when young, also some colic and projectile vomiting as an infant.

Fig. 13, Glucose tolerance curves for Case 12

P.E.: Wt. 97, Ht. 60", blood pressure 100/50, P.B.I. 4.8 mcg%. Swollen turbinates, crowded lower incisors, long right index finger, sluggish reflexes.

Diagnosis: Inborn error in metabolism, hypoadrenocorticism (mild), hypothyroidism (mild).

RX: Diet, Intramuscular A.C.E. (in oil), Proloid, Bellergal, B12, Theelin in small doses.

Course: Gradual improvement in personality and school work. Went from failing student to honor student. At age 17 however, indulged in sexual reveries almost hallucinatory in degree. Reported imaginary sexual debauches as fact. This has since cleared up.

GTT: 8/5/65; F-90, 1/2-168, 1-150, 2-127, 3-91, 4-85, 5-100, 6-109

8/30/66; F-90, 1/2-155, 1-160, 2-105, 3-90, 4-90, 5-87, 6-85.

Case 13

Patient: C.M. First seen 5/11/60; Age 66; White female. Repeated periods profound depression starting with menopause in 1943. Two courses of electroshocks - last one in 1954. Now on Nardil. Referred by psychiatrist as a "hopeless case."

Fig. 14, Glucose tolerance curves for Case 13

P.E.: Wt. 150, Ht. 64", blood pressure 134/70. Crowded lower incisors, long right index finger. Some pigmented moles. Positive Rogoff. Some pitting edema of ankles. Strongly exaggerated reflexes, marked Kraurosis vulvae.

GTT: 4/28/60: F-81, 1/2-143, 1 1/2-67, 2 1/2 -67, 3 1/2-70, 4 1/2-84.

Diagnosis: Hypoadrenocorticism, post-menopausal syndrome, autonomic nervous system instability, allergic diathesis.

RX: Diet, A.C.E.< Menagen, Bellergal, Theelin, Benadryl, B6, B12. Reduce Nardil. Librium later prescribed.

Course: Steady progress with fewer more shallow periods of depression at greater intervals until at the present she leads a very full life with much activity in the arts, education and travel. Endures stress extremely well. She has recently been awarded a high public honor.

Case 14

Patient: V.C. First seen 4/10/65; Age 17; White female. Tired and depressed. Frequent headaches, no interest in anything. Gets dizzy dressing, has to sit on bed. Cries for no reason. Can't concentrate. Panicked at college boards. Feels something terrible is going to happen to her. Hay fever history, also enuresis.

Fig.15, Glucose tolerance curves for Case 14

P.E.: Wt. 126, Ht. 64", blood pressure 118/74. Marked vasomotor rhinitis, some crowding of lower incisors, some hair upper lip, long index fingers, 4th interspace tenderness, positive Rogoff, overactive reflexes. P.B.I. - 6.2 mcg% (taking 1 gr. thyroid daily).

GTT: F-87, 1/2 - 115, 1-96, 2-115, 3-95, 4-78, 5-95.

Diagnosis: Moderate hypoadrenocorticism. Slight estrogen deficiency.

RX: Diet, A.C.E., Progesterone, Theelin, B6, B12, Norpramin, DOCA, Proloid, Librium.

Course: Stormy slow progress with candy binges and spells of depression, withdrawal, and banging head on floor. Attitude at times has approached catatonia. Has been able to work as a salesgirl and is better able to manage her depressions. Wants to go to college and has been admitted.

Case 15

Patient: H.W. First seen 1/19/66; Age 43; White male. Asthma, hay fever, "skin condition", rhinitis, started 22 years ago. Called "shrimp" as a boy. Sense of nervous compulsion. Colchicine etc. for gout one year ago. Lost sense of taste several years ago. Craves sweets. Haunted by continuous sense of anxiety.

Fig. 16, Glucose tolerance curves for Case 15

P.E.: Wt 137, Ht. 68", blood pressure 110/84. P.B.I. -8.7 mcg%. T3 1.09. Long index fingers, gouty deformation of the hands, crowded lower incisors, skin lesions back scalp and left sternum, engorged thyroid, pigmented nevae, Rogoff sign mod. pos., exaggerated reflexes.

GTT: 1/8/66: F-84, 1/2-98, 1 1/2-56, 2 1/2-46, 3 1/2-50, 4 1/2-53, 5 1/2-70.

PM Test: 11/4/66: F-73, 1/2-165, 1 1/2-96, 2 1/2-75, 3 1/2-44, 4 1/2-48, 5 1/2-56

Diagnosis: Marked adrenal insufficiency, autonomic nervous system instability, severe seborrheic dermatitis of scalp and torso, gouty arthritis.

RX: Diet A.C.E., Bellergal Spacetabs, Bellergal, B6, B12, Vitamin C, Testosterone, DOCA.

Course: Marked improvement in mental outlook, upsurge in ambition and energy output. Got very much improved. Rare headaches. Sense of smell returned. Asthma disappeared. Gave up smoking without noticing it. Seborrhea cleared completely and only pigmented areas remain on chest and lumbar area.

The aspect of the patient's present gratifying sense of general well-being is most important to him is at the same time the most interesting to the physician. For twenty years the patient has been operating successfully, writing books, mastering difficult engineering techniques and carrying a heavy teaching load. Now to his amazement the realization comes that throughout his adult life he has been driving himself mercilessly in the face of terrifying anxieties and discomfort. His present life is such a new and different experience that he doesn't see how he ever survived.

Case 16

Patient: L.E. First seen 12/9/64; Age 44; White female. Referred - already under treatment for hypoglycemia. Shaking and nauseated. Wakes at 3 AM with pain and severe palpitation. Two courses of electroshocks in July 1964. First one helped, second one made her feel worse - couldn't stand them. Thorazine makes her scream, kick, and pound. At various times has been dizzy, weak, nauseated. She has had shaking of the arms and legs, quivering inside. Crying, worried, depressed. Felt like screaming or dying. Masturbated as often as 30 times in one day. Treated in 1964 for hyperglycemia with orinase. Normal blood curve returned. Now "cries all the time, can't stand people or radio." Can't drive a car now - use to relax her. Can't take Bellergal. Inactive pulmonary tuberculosis.

Fig. 17, Glucose tolerance curves for Case 16

GTT: 1962: F-115, 1/2-189, 1-147, 2-147, 3-94, 4-42, 5-74.

11/21/66: f-92, 1/2-168, 1-144, 2-112, 3-76, 4-84, 5-84, 6-92.

Aug. 1964: F-81, 1/2-158, 1-153, 2-129, 3-119.

P.E.: Wt. 136, Ht. 66", blood pressure 128/82 T-3 1.06 Crowded lower incisors, long index fingers, 4th interspace tenderness, positive Rogoff sign. Progesterone obesity.

Diagnosis: Marked hypoadrenocorticism, hypo-ovarianism (estrogen and progesterone deficiency), marked vagal involvement (damaged by TBC chest surgery).

RX: Diet, A.C.E., Theelin, Durabolin, B6, B12, Belladonna, Quindine, Menagen, Norlutin, Quinaglute, Norpramin, Valium, Calcium Benadryl, Ascorbic Acid.

Course: Signs and symptoms dropped away one by one. Shaking and quivering ceased. Mood improved and crying stopped. Masturbation ceased. Took up automobile driving again. Fondness for music returned. Took part in an amateur entertainment and was offered some professional contracts. This after being certified for long-term complete disability.


More than twenty years ago Selye (1946), Long (1940), and Britton (1932) reported animal experimentation with A.C.E. that convinced the writer that the hypoglycemia which follows glucose intake is caused primarily by failure of the adrenocorticosteroids to inhibit insulin activity and influence the rate of insulin catabolism (Ingle, 1944). This hypothesis has been corroborated recently by experiments which indicate that insulin induced hypoglycemia stimulates the productions of glucosteroids by the adrenal cortex (Plager & Matsui, 1966). The insulin level reached is not high enough to justify the term hyperinsulinism. It was concluded that the activation of the hypothalamic-pituitary-adrenal system is not so much a function of the fall in blood glucose below an absolute level as it is of the rate of glucose fall. This reaction is modified by the initial level of blood glucose. The GTT is therefore a delicate indicator of the ability of the C.N.S. and especially of the hypothalamus to activate the neural and humoral pathways to the pituitary. In pituitary failure there is no response to insulin administration even though the rate of blood glucose could be sufficient to produce adrenal response in cases with intact pituitaries.

Within the past year. Plager and Matsui (1966) have demonstrated in vitro what has been postulated in vivo that there is a graded antagonism between various dose levels of cortisol and insulin. Unfortunately, current animal experimentation does not deal with the whole extract since cortisol is generally presumed to be the principal ingredient in such a preparation and therefore there is a dearth of recent laboratory data on the obvious synergistic-plus-antagonistic activity of the whole extract. However, this writer has reported repeatedly and at some length on the highly beneficial results obtained in 25 years of clinical use of A.C.E. (Tintera & Lovell, 1949; Tintera, 1955; Tintera 1966).

As we know, the human organism operates for the most part on glucose which must be supplied by the blood at the appropriate concentration. It is understood that the adrenal cortex, through the operation of the glucocorticoids plays a major role in regulating this concentration but there are many intricate systems involved in carbohydrate metabolism; particularly enzyme systems of the "Kreb's cycle". These operate in all tissues at the cellular level, especially in the muscles and the liver. The enzymes of the liver necessary for glycogenolysis and gluconeogenesis have been identified. Alcohol dehydrogenase and other enzymes implicated in psychopathological conditions have been less thoroughly investigated although they play a role in alcoholism and drug addiction.

The other organs participating in carbohydrate metabolism have received too little attention. For instance, the prostate is responsible for the metabolism of fructose. Chronic benign prostatic hyperplasia is a frequent concomitant of schizophrenia and is not necessarily an erotic manifestation. Roberts (1966) has pointed out that the intactness of the testis, the pituitary and the adrenal is necessary for accelerated prostatic growth. Prostatic hyperplasia can be exaggerated by the increased elaboration of growth hormone, adrenocortical steroids and pituitary prolactin or interstitial-cell stimulating hormone under the repeated stimulus of recurrent hypoglycemia. Androgens exert a diabetogenic effect as do these counter-insulin responses. The high zinc, fructose, and enzyme content of the prostate favors the production of insulin and thus may induce hypoglycemia.

The kidney contributes perhaps 15-20% of the inflow of glucose as calculated from arteriovenous differences and renal blood flow (Cahill, 1964). This will be discussed below:


The importance of diet in the treatment of hypoglycemia (Physician's Guidelines, 1966) cannot be overemphasized. There must be strict elimination of all rapidly absorbable carbohydrates. This forestalls the sudden rise and subsequent fall in blood sugar levels. The heightened protein intake is beneficial in its own right since individual amino acids evoke rises in circulating glucose (Fagans, Unp-Lecture).

Vitamin intake should be monitored to facilitate proper liver (B6) and adrenal function (B1, 2, 6, 12, & C). Ascorbic acid is particularly important since adrenal requirements for this vitamin are greatly increased by stress.

In most instances if tranquilizing agents have been prescribed they may be reduced in dosage when agents influencing the autonomic or vegetative nervous system are prescribed. The A.N.S. undoubtedly plays a major part in converting emotional stimuli into symptoms. In order to minimize the role of emotions in the production of functional symptoms in patients with adrenal insufficiency, it has been found advisable to prescribe a combination (Bellergal) of 1-hyoscyamine, ergotamine tartrate and phenobarbital. Large doses of this preparation are not required because of a synergistic action with adrenal cortical extract. Patients are generally started on three tablets a day, one on arising, one at about two o'clock in the afternoon before the expected fall in blood sugar, and then one between dinner and retiring. Portis has demonstrated that paralysis of the right vagus nerve with large doses of atropine will prevent the inevitable fall in blood sugar (Portis, 1950; Portis & Zitman, 1943). After approximately one to two months the Bellergal may be reduced to two tablets daily. This dosage has been continued for as long as six years. this autonomic system-oriented preparation helps reduce the intensity of emotional stimuli, thus acting to prevent the development of functional disturbances. In my estimation this is one of the most valuable drugs available to the physician.

In mild cases at least 10 cc. of A.C.E. are given intravenously (or if practical, intramuscularly) at least once a week for one to two months. In severe, acute cases 10 cc injections may be required as often as every four hours for the first 24 hours; the q. 8 hr. until it seems clinically possible to give daily injections which may be continued for 1-2 weeks. After that, weekly injections may be given indefinitely until the interval between treatments may be progressively increased to two weeks, three weeks, etc. Pyridoxine, 1.0 cc (50 mg.) is added to the solution of A.C.E. at least once a week because of the role of this vitamin in the enzyme systems involved in regulating carbohydrate metabolism. Also for its synergistic and antihistaminic sedative effect, the optional addition of 1 to 5 cc of Benadryl hydrochloride solution to the intravenous infusion is sometimes desirable.

The use of A.C.E., especially if given intravenously, produces a temporary feedback inhibiting the pituitary from whiplashing an already exhausted adrenal and gives a refractory period of about fours hours to the cells in the zona fasiculata and zona reticularis. At the same time, the level of circulating glucosteroids is elevated so that restorative processes can take place in the liver. With stabilization of the blood sugar, the over-stimulated pancreas is also given a period of respite. However, if cortisone or one of its derivatives is given in place of A.C.E., this steroid would have to be given in divided doses of at least 100 mg. or its equivalent, which would completely inhibit the pituitary and thus the secretion of glucosteroids by the cells of the zona fasiculata and if given over an extended period, atrophy of these cells would occur and further adrenal insufficiency would result. In fact, continued use of individual glucosteroids will invariably increase the level of blood glucose so that diabetic levels develop.

ACTH is also contraindicated in these patients since it would tend to whip the already exhausted adrenal cortex, producing hypertrophy and possibly hyperplasia of the cells of the zona fasciculata, but with little beneficial effect upon the mineralosteroid-producing cells in the zona glomerulosa save for further slight water retention.

For males - Testosterone proprionate 50 mg. I.M. once a week initially and methyl testosterone (Oreton) 19 mg. b.i.d. -- p.c. daily buccal administration - no more than 2 gm. over a 3 month period. To help restore nitrogen balance and further reduce demands on the adrenals - Adroyd or Maxiboten may be used. When intervals have been increased to one month, 1cc Decadurabolin may suffice to maintain a positive nitrogen balance.

For females - after negative Pap smear and culpocytology - Theelin or conjugated 5 mg. (50,000 i.u.) weekly injections, and natural estrogens (Menagen or Premarin) orally daily (during child-bearing years from the 3rd through the 26th day of menstrual cycle). If there is a history of fibroids or dysmenorrhea, progesterone may be beneficial in addition to the estrogen (from the 12th through the 26th day of the menstrual cycle).

Some comment is indicated on the various medicaments mentioned in the foregoing resumes. There seems to be some misunderstanding as to the use of the whole natural adrenal cortical extract (A.C.E.). It is uniquely valuable and safe (Mod. Drug Encyl., 1965). In addition, it is effective for long term use and in many cases should replace the corticosteroids. To our personal knowledge more than 50,000 individual doses (10 cc or more) have been administered over 20 years with no report of undesired side effects and with consistent reports of beneficial results, often dramatic. In extreme cases or in conjunction with surgery, dosage may be as high as 200 cc so long as salt intake is maintained. Lipo Adrenal Cortex is also available for intramuscular use. One cc of this preparation is equal to 10 cc of the aqueous extract.

Bellergal has been dealt with elsewhere at some length. Other drugs are of special interest mainly because of unwanted or toxic side effects. Large doses of chlorpromazine for instance over a long period will substantially reduce the secretion of ACTH (Bass, 1965). Hepatic toxicity (jaundice) (Fajans Unpl. Lecture) has been reported from isocarboxazid (Marplan), phenelzine sulfate (Nardil), imapramine hydrochloride (Tofranil), and desipramine hydrochloride (Norpramin, Pertofrane). Many reports have dealt with hypertensive reactions resulting from the ingestion of cheese while taking any of the monoamine oxidase inhibitors: Marplan, Nardil, nialamide (Niamid), tranylcypromide (Parnate). The antidepressants should not be prescribed for patients with epilepsy or impaired kidney function.

The minor tranquilizers, chlordiazepoxide (Librium), chlormezanone (Trancopal), diazepam (Valium), and meprobmate (Miltown-Equanil, etc.) can cause less severe but definite adverse hepatic and renal effects.

Since hypoadrenocorticism is characterized by hyponatremia and hypo-kalemia, these side-effects must be kept in mind. Hyponatremia, a factor in the "Inappropriate Antidiuretic Hormone Syndrome," causes headache, disorientation, somnolence and other cerebral symptoms. Severe headaches often accompany the alkalosis associated with hypokalemia. Pending electrolyte adjustment these can be relieved by glutamic acid-hydrochloride in doses large enough to acidify the urine. As we have seen, the kidney in man contributes perhaps 15-20% of the inflow of glucose. Any agent which would depress renal glycogenesis could theoretically result in symptomatic hypoglycemia within an hour (Roberts, 1966). It is well therefore when prescribing any of these drugs to be alert to possible toxicity for the liver, kidney, and cerebrum.

When the hypoglycemia of hypoadrenocorticism associated with schizophrenia has been recognized, the administration of A.C.E. and the institution of appropriate diet and supportive medication will fill only the immediate needs of the patient. At this point the talents of the psychiatrist are vital. His approach may be altered somewhat but the guidance of the physician-psychiatrist is of prime importance in the restoration and maintenance of the desired homeostatic state, the reflection of the nutritional, hormonal, and nervous function of the body. The psychiatrist must lead these physiologically inadequate and often emotionally immature individuals to full maturation by regulating their activities and guiding them in their adjustment to society and in the acceptance of their limitations and in the avoidance of stressful situation.


The individual with constitutionally inadequate carbohydrate metabolism has been described as the potential and genetic candidate for schizophrenia.

Recognition is most easily made through correlation of symptoms and readings during a five-hour glucose tolerance test, and the interpretation of the curve (Tintera, 1966).

Although many mentally or emotionally disturbed individuals seem to make adjustment through diet alone, the underlying hypoadrenocorticism must be treated. The regime of choice includes A.C.E., ancillary hormonal therapy, supportive medication, and personal counseling.


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