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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.
Reprinted from NEW YORK STATE JOURNAL OF MEDICINE, Vol. 55, No. 13,
July 1, 1955, Copyright 1955 by the Medical Society of the State of New
York and reprinted by permission of the copyright owner.
The Hypoadrenocortical State and Its Management
John W. Tintera, M.D., Yonkers, New York
(From the Endocrine Clinic, St. John's Riverside Hospital)
In a select recorded group of 200 subjects studied over the past fifteen
years, the varied symptoms exhibited, suggested some phase of adrenocortical
dysfunction: either lack of adequate adrenal cortical hormone production
or an imbalance among these hormones. Essentially, all of the symptoms
seemed to have some bearing on the integrity of the adrenal cortex and
responded, in effect, to the same mode of therapy. This report will use
the conveniently designated topic of hypoadrenocorticism, and elaborations
around it will be on the practical plane.
Etiology and Pathogenesis
Simply stated: hypoadrenocorticism is Addison's disease. The usually
encountered case dealt with herein is actually "subclinical Addison's
disease." By thus defining it, a former hypothesis - that the adrenal
cortex functioned according to the classic "all or none" law
- is repudiated as being contrary to both clinical and experimental evidence.
Hypoadrenocorticism may be congenital or acquired, complete or partial.
The two former subdivisions frequently fail of recognition. An etiologic
classification, therefore, also derives from practical considerations:
1. Constitutional or primary hypoadrenocorticism
2. Congenital hypoadrenocorticism
3. Secondary hypoadrenocorticism
B. Acquired hypoadrenocorticism
2. Steroid therapy (cortisone and hydrocortisone)
CONSTITUTIONAL OR PRIMARY HYPOADRENOCORTICISM - The constitutional type
may be a Mendelian trait. Because it is most common, it typifies subjects
discussed in this paper. The cognitive, characteristic asthenic habitus,
peculiar idiosyncrasies and sensitivities, longevity, etc., may be traced
in the family history, maternal, paternal, or both.
CONGENITAL HYPOADRENOCORTICISM - This type is encountered in the infant whose mother is deficient in adrenal cortical secretion. During pregnancy the adrenal of the growing fetus and placenta apparently supplement the mother with the necessary adrenal hormones. It may be presumed that the fetal adrenals can be thus depleted. Infants manifesting such adrenal insufficiency often die neonatally: "pyloric stenosis" has been so ascribed. Others may manifest hypoadrenocorticism only as they grow older with the deficient gland inadequate to ordinary stress (See Note)
(Note) Natelson, et. al.  studied the "immature infant"
and observed that "adrenal immaturity" is a common finding in
the premature infant. They use the term to denote a condition resulting
in the inability of the infant to hold water, sodium ion, and chloride
ion with no unequivocal histological or pathologic evidence to show the
adrenal involvement. It has also been found that the thymus gland does
not regress in children with immature adrenals. Since hypersecretion from
a stimulated adrenal during the alarm reaction does cause thymic involution,
it is logical to treat status thymicolymphaticus with adrenal cortical
SECONDARY HYPOADRENOCORTICISM (Hypopituitarism and Acquired Hypoadrenocorticism).
- Hypofunction of the anterior hypophysis produces a variety of clinical
pictures, depending on the amounts of specific tropic hormones produced,
and so we may find hypoadrenocorticism as the result of such a condition
flowered by symptoms of other glandular malfunctions.
Aside from cases resulting from hypopituitarism and steroid therapy,
individuals subjected to great stresses, such as those referred to by Selye
 in his "general adaption syndrome" (G.A.S), may develop hypoadrenocorticism.
In these instances the glands work beyond their capacity, passing through
the alarm reaction, the stage of resistance, and finally reaching the stage
Symptomatology and Diagnosis
The chief or presenting complaints, associated symptomatology, related
systemic disorders, and physical and laboratory findings are given in Table
I. The order of percentage frequency by which they are tabulated is based
on convenience for presentation (a few of the percentage assignments are
based on a smaller sampling since these, emerging only as the series progressed,
were not sought for and elicited except in more recently studied patients).
However arbitrary this tabulation, its perusal reveals one significant
fact. The chief complaints listed for patients with hypoadrenocorticism
are often similar to those found in persons who are in the hypoglycemic
state. Patients finally adjudged to be hypoadrenocortic invariably
report feelings of weakness, fatigue, and faintness, all of which could
result from periods of low blood sugar level, usually extant. These periods
of hypoglycemia are exacerbated by and follow bouts of emotional upsets
after the initial hypoglycemia. In a series of business executives, Portis
 has shown that hypoglycemia is definitely related to emotional stress.
He suggested that the emotional centers which are exposed excessively to
these stress transmit impulses which cause overactivity of the parasympathetic
system. This heightened vagal response stimulates the islet cells of the
pancreas. Hyperinsulinism, which produces a low blood sugar level, develops
from the stimulation of the islet cells.
TABLE I. - Symptomatology in 200 Cases
PerCent of 200 Cases
Fatigue (excessive) 94
Nervousness and irritability 86
Mental depression 79
Weakness (excessive) 65
Faintness or fainting spells 42
Craving for salt 84
Craving for sweets 75
Alcohol intolerance 66
Epigastric distress 51
Food or drug idiosyncrasies 47
Alternate diarrhea and constipation 45
Chronic colitis 4
Premenstrual tension 85
Midperiod slowing 33
Pain in sternomastoid and trapezius muscles 65
Inability to concentrate 77
Fears and apprehension 65
Confused intervals 61
Poor memory 59
Feelings of frustration 56
Compulsive behavior 38
Associated or Possible Resulting Conditions
Hay Fever 23
Skin dermatitides 39
Heat exhaustion 36
Rheumatoid arthritis 21
Rheumatic fever 7
Findings on Physical Examination
Postural hypotension 93
Generalized cervical lymphadenitis 93
Skin thin and dry 91
Perspiration scanty 91
Hair sparse 83
Typical denture formation 80
Asthenic habitus 78
Positive Rogoff sign 71
Redness of thenar and hypothenar eminences 28
Blanching on exposure to cold 21
Low basal metabolic rate (average - 12) 85
X-ray J-shaped stomach and visceroptosis 73
Glucose tolerance test (low flat curve) 51
Relative lymphocytosis 51
Male (2.4 to 29; average 10.9 mg. per 24 hours)
Female (1.2 to 22; average 7.7 mg. per 24 hours)
* Theses are hypoglycemic in nature and tend to follow physical, mental, or emotional stress.
Whether the low blood sugar in the patient with hypoadrenocorticism
is a result of similar autonomic manifestations remains undetermined. It
may well be the case, however, since this type of patient is emotionally
labile and responds vigorously to crucial stressful situations. Many of
our patients show a glucose tolerance curve which forms practically a straight
line at a low level. However, if the adrenals have been subjected to increased
stress through indiscretions, e.g., high carbohydrate intake or abuses
through alcohol or other toxic agents, changes occur in the liver so that
a condition of fatty infiltration or degeneration ensues. With this situation
a sudden rise in the blood sugar level as high as 300 or 400 mg. per 100cc
of blood may occur, followed by a sudden drop to hypoglycemic levels. It
is this sudden drop which usually precipitates symptoms.*
*Striker  has demonstrated that a patient maintaining a blood sugar
of over 400 mg. had definite hypoglycemic reactions, pointing out that
it is the suddenness of the fall in blood sugar which produces general
reactions and not the level from which or to which it may have fallen.
Diagnosis should be possible from the history and symptomatology, together
with the glucose tolerance curve and complete blood count. Inability to
concentrate, loss of memory, mental depression, insomnia, periods of irritability,
and a tendency to negativism and other personality aberrations are to be
regarded as significant. Of pathognomonic significance, these patients
are usually of the constitutionally inferior asthenic type, often falling
in the allergic diathesis group, usually revealing a positive Rogoff Sign,
relative lymphocytosis, and a typical low glucose tolerance curve. However,
these findings may be masked, for example, in the patient who has a superimposed
gonadal deficiency, with its typical obesity, or an altered glucose tolerance
curve in an advanced case with hepatic damage. In addition, a history of
great longevity without senility of the forebears is obtained.
Since the gastrointestinal system is particularly sensitive to emotional
stress, many symptoms involving the digestive tract are reported. Chief
among these is a dull ache or dragging or gnawing sensation in the epigastrium.
With upset of carbohydrate metabolism pain or distress may occur in the
epigastrium referred from the liver. In addition, these patients often
have alternate periods of diarrhea and constipation. Their stools are frequently
in the form of sclybala, and chronic mucuous colitis or chronic ulcerative
colitis may develop. Bercovitz , in his treatment of ulcerative colitis
with adrenal cortical extract, states that, "It is quite obvious from
even a casual observation of these patients that they are deficient in
their adrenal cortical output."
GENITOURINARY COMPLAINTS - The menarche has its onset somewhat later
than average, and although it occurs regularly, there is an atypical flow
lasting about seven days with profuse bleeding. In 33 percent of the cases
the peculiar aspect of this type of flow was that it ceased on about the
fourth day almost completely or with just slight staining, started up again
profusely on the fifth or sixth day, and then slowed up or stopped on the
seventh. Eighty-five per cent of the women had premenstrual tensions with
such manifestations as nervousness and emotional instability, headaches,
and the accentuation of carbohydrate craving and, particularly in the alcohol
group, an almost uncontrollable desire to start drinking again. Dysmenorrhea
is a frequent complaint because of infantile uteri, markedly retroflexed
or retroverted. These small uteri may the cause of the repeated spontaneous
abortions recorded in this series. It is possible that the abortions result
from the fact that although the fetus grows at a normal rate, this rate
is disproportionate to the rate of development of the uterus.*
*Pertinent to the assignment of abortion tendency in this category of
patient is the fact that most effective treatment has been found to be
estrogenic hormones and adrenal cortical extract administered during the
first eight months of gestation.
Most of the men were found to have normal sexual development. The secondary
sex characteristics, aside from the hair distribution, were normal. In
Timme's syndrome, in addition to an adrenal insufficiency, there is a persistence
of the thymus together with a gonadal deficiency, accounting for the low
blood pressure, hypoplasia of the heart and vessels, and the characteristic
scrotal fold surrounding the base of the underdeveloped penis in preadolescent
boys. At times in this latter condition there is an abnormal bony structure
simulating that seen in Paget's disease. In chronic alcoholism many cases
of gonadal atrophy and gynecomastia were observed resulting in sterility
or loss of libido.
PERSONALITY MANIFESTATIONS - Hypoadrenocortical patients are usually
very meticulous in all of their work. They are perfectionists who often
drive themselves to exhaustion since they do not know the meaning of the
word "relaxation." Their greatest period of activity occur after
meals. Sluggishness, lack of concentration, etc., occur just prior to lunch
when the blood sugar is at a low ebb. There is a feeling of well-being
after eating, but symptoms again become severe at about 3:00 or 3:30 in
the afternoon. This depression can be alleviated in approximately twenty
minutes by eating a bar of candy, but unfortunately, an even greater period
of depression is experienced an hour or two afterward. Of much greater
value would be the ingestion of a glass of milk or some fruit at this time.
These patients feel best after their principal meal in the evening, and
this feeling of well-being lasts for several hours. Mor profound personality
involvements are seen in some patients with actual schizoid tendencies,
particularly in the younger individuals, and gratifying results were obtained
with the treatment to be outlined later. These severe personality defects
had been previously classified as schizophrenia, manic depression, and
As previously noted, hypoadrenocorticism is often seen in children either
or both of whose parents has an adrenal insufficiency. The most outstanding
change in such a child is the development of an abnormal craving for carbohydrates.
This desire for candy and sweets may be so intense as to be the basis of
so-called "behavior problems." In addition, many children complain
of suffering from "growing pains." These may conceivably be early
manifestations of the rheumatoid type of arthritis which is seen in adults
It is important to emphasize the fact that individuals of all ages suffering
from hypoadrenocorticism can undergo severe personality and emotional changes
but which, fortunately, in most instances are reversible.
In studying juvenile delinquents it is well to evaluate the glandular
setup of the individuals before passing judgment on their antisocial acts.
Included in this series were children considered as serious behavior problems
but who responded dramatically to proper regulation of diet with a minimal
amount of hormone therapy. Many children were reported to have a high I.Q.
but still failed in their scholastic studies, particularly mathematics,
which requires concentration, and who after therapy became outstanding
honor students. Abnormal sexual behaviors, as exhibitionism and homosexuality,
responded favorably if accompanied by adequate psychotherapy.
Alcoholism as a Manifestation of Hypoadrenocorticism
Two distinct groups of alcoholic patients have been observed. The first
group comprised individuals who were typical of hypoadrenocorticism, e.g.,
asthenic in habitus, little or no chest hair, hypotensive, and not infrequently
gynecomastic. These patients had varying degrees of hypoadrenocorticism
manifested by hypoglycemia, low titer of 17-ketosteriods, etc. Such patients
were found to have a constitutionally low tolerance to alcohol and were
considered as likely to become alcoholics at an early age. The second group
had non pre-existing hypoadrenocorticism but, though alcoholic indulgence,
caused damage to the adrenal cortex and to the other glands involved in
the metabolism of carbohydrates. These alcoholic patients nearly always
exhibited hypoglycemia during their dry periods. 
We believe that when the blood sugar falls to a certain low level, a
craving for alcohol results. Actually, this is a craving for sugar, but
these patients inherently know they will respond quicker to the intake
of alcohol. Continued drinking produces three changes: (1) eventual decrease
of the blood sugar, (2) depletion of the liver glycogen stores, and (3)
fatty infiltration of the liver.  In this state the liver is unable
to detoxify the estrogens, and sex changes found in chronic alcoholism
result, e.g., gynecomastia, loss of body hair, and gonadal atrophy.
APPEARANCE - The appearance of hypoadrenocortical patients is very characteristic.
They are usually tall, fair, and asthenic and have a full head of very
fine and abundant hair. The hair distribution on the body, however, is
rather sparse. In males, the hair on the lower lateral two thirds of the
legs is usually absent with little or none on the chest, and there is often
delay in the start of shaving. The palms of the hands show a marked reddening
of the thenar and hypothenar eminences, and in some patients even the tips
of the fingers become very brilliant red. The nails are brittle, which
may be accentuated if the patient has been subjected to prolonged periods
of stress. The skin is thin and dry, but there may be increased sweating
of the palms and axillae. There is frequently an easy bruisability as a
result of increased vascular fragility. Constitutional therapy as described
later has been most effective in clearing such conditions as infantile
eczema and, in later life, the neurodermatitides, circumscribed or disseminated,
as well as other allergic symptoms of these patients who fall into the
allergic diathesis group. These include asthma, allergic rhinitis, hay
fever, urticaria, psoriasis, and ichthyosis.
BLOOD PRESSURE - A hypotension is usually found in association with
a droplet shaped heart. Postural hypotension is usual in that the blood
pressure may be 105/60 on standing and may be elevated to 120 or 130/70
or 80 on reclining. This is considered to be the reason why many patients
find it difficult to fall asleep and reading in a semireclining position
for fifteen to twenty minutes for fifteen to twenty minutes is very conducive
POSITIVE ROGOFF'S SIGN - When pressure is applied over the adrenal area
(junction of lower rib erector spinae muscles), a very definite tenderness,
with some patients experiencing excruciating pain, may be elicited.
SWELLING OF THE EXTREMITIES - This symptom is found in alcoholics, arthritics,
and many other cases of hypoadrenocorticism. It is probably a result of
changes in the sodium-potassium relationship. It responds readily to therapy
and occasionally to the simple expedient of providing additional salt to
the diet. In our patients we have observed ankle edema resulting from poor
peripheral circulation, particularly with a sudden change in temperature
or atmospheric pressure. Some may have a marked puffiness of the lower
lids upon awakening which does not subside for several hours or until the
circulation has improved by activity. Several cases of nephrosis in children
with marked generalized edema and ascites, included in our series, have
responded to the general treatment as outlined for hypoadrenocorticism.
PIGMENTATION - Generally, hyperpigmentation of the skin or palmar creases
is not a consistent finding. In several cases, including two children with
nephrotic syndrome, an almost black discoloration of the entire skin faded
within two weeks of therapy. Other cases had vitiligo without demonstrating
the severe symptoms of Addison's disease.
LOW BLOOD SUGAR - Much information can be obtained from the glucose
tolerance test. It is helpful in evaluating the condition of the liver
(reaching hyperglycemic levels), pancreas (hypoglycemia), adrenal cortex,
and pituitary (low flat curve).
LOW BASAL METABOLISM - Some texts have referred to this condition as
being an atypical hypothyroidism because of the regular incidence of a
low basal metabolic rate. In almost all these cases a basal metabolic rate
of -11 to -15 is found. A low basal metabolic rate is not necessarily an
indication for thyroid medication, especially since these patients have
been found to be extremely sensitive to thyroid extract, a fact which can
be explained by the physiologic relationship between the thyroid and the
LOW TITER OF 17-KETOSTERIODS - Another indication of adrenal involvement
is the low titer of 17-ketosteriods. The normal range is 12 to 15 mg in
men and 8-10 mg. in women, whereas in these patients we may find 3 to 12
mg. in men and 2 to 8 mg per twenty-four hours in women. However, much
higher levels are possible if the determination is made at a time of stress
BLOOD COUNT - A relative lymphocytosis (35 to 55 per cent), an eosinophilia
(1 to 9 per cent), and a moderated neutropenia have been recorded in our
OTHER TESTS - These include the Robinson-Kepler-Power water test and
its modifications by Soffer and Gabrilove and, more recently, by Oleesky,
the Thorn eosinophil test; the salt deprivation test; the prolonged fast;
the intravenous glucose tolerance test; and the insulin sensitivity test.
These usually give corroborative information but are not to be considered
as diagnostic; and moreover, the latter four may entail some danger to
the patient. Equivocal values have been obtained in determination of the
serum sodium, potassium, and chlorides as well as urinary 17-hydrocorticoids,
However, electrocardiographic observations in hypoadrenocorticism and particularly
in acute or chronic alcoholism reveal a lowering or inversion of the T
waves indicating hyperkalemia which disappears after a few days treatment
with adrenal cortical extract.
Grouping of Adrenal Steroids
Every symptom of hypoadrenocorticism may be accounted for by a particular
group of hormones produced by the adrenal cortex, of which about 28 have
been isolated. These hormones may be divided into three groups:
1. Glucosteroids: These steroids function principally in the control of carbohydrate (and protein) metabolism. Failure to utilize sugar properly is the chief cause of symptoms in this syndrome.
2. Mineralosteroids: The water-salt balance of the body is dependent upon these steroids; the imbalance resulting from the excessive excretion of urinary sodium and cellular retention of potassium accounts for the lack of perspiration, craving for salt, and characteristic electrocardiographic findings.
3. Sexogens or 17-ketosteriods: These include the estrogens, androgens,
and progesterone-like compounds, any one or combination of which may alter
the sex characteristics of the individual.
Treatment of Hypoadrenocorticism
Because the symptoms of hypoadrenocorticism are often so similar to
those found in patients with purely psychosomatic disorders, differentiation
between those on a psychic basis and those resulting from an adrenal insufficiency
is necessary. A complete history, thorough physical examination, and indicated
laboratory tests are usually sufficient. In this category of patients treatment
should be started only after a diagnosis has been reached through an evaluation
of the facts and results obtained from them. In certain urgent categories
the therapeutic test must antecede final diagnostic evaluation.
It has been observed that patients respond more rapidly to treatment
if they are given a complete but simple explanation of the nature of their
illness. Patients with hypoadrenocorticism are subject to various stresses
and must be told how they are harmfully affected by such things as dietary
indiscretions, fatigue, worry, etc. They will adjust their activities and
keep to the prescribed diet more willingly if they understand how emotions
can produce symptoms and how excessive carbohydrate intake produces their
feelings of fatigue and weakness following a short period of well-being.
Once the nature of their condition has been discussed, the three aspects
of treatment may then be instituted.
ADJUSTMENT OF ACTIVITY - Many of these patients have worked out routines
for themselves which may help in controlling their symptoms. They soon
realize that they can prevent hypoglycemic reactions by eating between
meals, taking snacks before retiring, eating less at mealtime, etc. A number
of them have learned to avoid eating candy because the transitory respite
is offset by the ensuing aggravation of symptoms. The most difficult part
of their readjustment is to learn how to avoid fatigue. They must be taught
how to take environmental and emotional stresses in stride. Many learn
to reduce their activities; others, through discussions of a psychotherapeutic
nature, soon change their attitudes and ideas. This aspect of treatment
is most important and probably most difficult to achieve quickly and successfully.
DRUG THERAPY - [[Note, Note: Adrenal Cortical Extract (ACE) is no longer
available in the United States]] The primary aim is to put the adrenal
cortex at rest temporarily in order to allow the cells to return to a functioning
state so that subsequently they may respond normally to stress. Sufficient
amounts of adrenal cortical extract are given so that the target organs
depending on these hormones are adequately supplied to return to normal
function. Depending upon the severity of the condition 10 cc. of adrenal
cortical extract are administered intravenously at varying intervals ranging
form every four hours initially to as long as once a week. Eventually the
patient may be expected to progress satisfactorily without the injections,
providing there is no undue abuse of any one or combination of the factors
discussed, i.e., diet, emotional and physical exertion. As the signs of
adrenal cortical insufficiency diminish, the dosage of adrenal cortical
extract is gradually reduced. Drug therapy application utilizes not only
adrenal cortical extract but also autonomic blocking agents as well. Their
respective operations are elaborated:
Adrenal Cortical Extract - This tends to adjust carbohydrate
metabolism by supplying glucosteroids, to correct water-salt imbalance
through its mineralosteroid activity, and to mediate secondary sex characteristics
which are controlled by the precursors of the 17-ketosteroids. Once the
symptoms of adrenal insufficiency are alleviated, the adrenal cortical
extract is curtailed, being reinstituted if indicated at the time of periodic
Agents Influencing the Autonomic Nervous System - The autonomic
nervous system 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 of 1-hyoscyamine, ergotamine
tartrate, and phenobarbital (Bellergal). Large doses of this preparation
are not required because of a probable 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. After approximately
one to two months the Bellergal is reduced to two tablets a day and then
to one tablet daily. This dosage has been continued for as long as six
years. This autonomic preparation helps reduce the intensity of the emotional
stimuli, thus acting to prevent the development of functional disturbances.
DIET - We cannot overemphasize the importance of a proper diet. These
patients will usually adhere to the prescribed diet, once they realize
from our discussion that dietary indiscretions will cause an exacerbation
of their symptoms. The diet essentially consists of the strict elimination
of rapidly absorbed carbohydrates in order to obviate the sudden rise in
blood sugar with its subsequent fall. Between meals, feedings of milk or
fruit are advised to prevent any slackening off of blood sugar levels,
which are prone to occur two to three hours after eating. Salt is allowed
in unrestricted amounts because of the tendency to sodium depletion. During
hot weather we advise supplementary salt in the form of tablets to replace
the loss caused by perspiration. The following is a list of foods permitted
and to be avoided:
All meats, fish, and shell fish
Dairy products (eggs, milk, butter, and cheese. Also recommended - 1 pint to 1 quart of acidophilus milk daily)
Milk between meals; milk, cheese, and/or butter and saltines before retiring
All vegetables and fruits not listed below
Salted nuts (excellent between meals)
Sanka, weak tea, and sugar-free soda
Soybeans and soybean products
Sucaryl as a substitute for sugar
Foods to Avoid
Potatoes, corn, macaroni, spaghetti, rice
Pie, cake, pastries, sugar, candies
Dates and raisins
Cola and other sweet soft drinks
Coffee and strong tea
All hot and cold cereals (except occasionally oatmeal)
The thesis that hypoadrenocorticism is a syndrome entity has been made.
Its symptoms typify those found in adrenal cortical disease. The usual
case presents those of a subclinical degree. While many of the latter point
to emotional instability, they are primarily functional in nature and actually
can be considered as being directly attributable to a hypofunction of the
adrenal cortex. Adrenal cortical hormones have been shown to play vital
roles in maintaining homeostasis in many abnormal conditions involving
stress, and therefore, the adrenal cortex appears to control this homeostatic
mechanism of the body.
The use of the whole adrenal cortical extract in the treatment of adrenal
disease, neglected since the development of adrenocorticotropic hormone
and cortisone, is herein re-emphasized. It must be pointed out that these
latter agents produce dramatic and permanent results only in such acute
conditions as, for example, delirium tremens, certain ophthalmologic diseases,
and other emergency crises, but the results are only temporary in chronic
conditions, specifically the collagen diseases.
Unfortunately, adrenal cortical extract therapy has been employed empirically
regardless of clinical observations and with apparent lack of rationale.
However, with adequate dosage many conditions under the heading of "hypoadrenocorticism"
have responded favorably. But, it has been argued, the amount of beneficial
glucocorticoids (cortisone) in 10 cc of adrenal cortical extract is minimal
and of about the order of 1 mg. of cortisone-like activity. Why then should
such good therapeutic results be obtained with it?
As yet, no reliable laboratory test have been devised to determine adrenal
cortical activity, particularly when the gland has not been damaged by
infections or toxic agents. Clinically we have shown that the activity
of adrenal cortical extract is far above that which is expected from its
ascribed cortisone content. From our own clinical observations we fee that
there is something physiologic about adrenal cortical hormones, whereas
the current literature is increasingly warning us that there is something
very unphysiologic about cortisone.
No one has yet distinguished between the effects of adrenal cortical
insufficiency and adrenal cortical imbalance. It would be perfectly possible
to have sufficient amounts of "S" and "N" hormones,
as Albright classifies them, yet if one were present in excess of the
other, the mutually antagonistic forces would be upset and would give rise
to clinical signs. Cortisone, hydrocortisone, or glucocorticoid substances
apparently alleviate certain disease processes, probably via biocatalytic
modification of enzyme systems. That is to say, it is not cortisone specifically
but glucocorticoid activity that gives beneficial results in relieving
most of the symptoms of Addison's disease. Who knows whether nor not other,
still unisolated corticoids will not prove to have still greater activity
along these lines and that they may be suppressed or minimized by creating
an artificial imbalance by the injudicious use of synthetic steroids.
Aside from the possibility of artificially creating an imbalance, we
must also consider the effects of indiscriminate exclusive steroid medication
on tropic influences. ACTH is now almost universally viewed as the tropic
hormone for cortisone. Is it also to be considered the tropic influence
for the other 27 steroids, or do these compounds appear solely as a physiologic
response to the needs of the body? The evidence is more and more pointing
to the fact that specific steroids may require specific tropic hormones.
Selye feels that somatropic hormone (STH) may be a tropic hormone for
the adrenal cortex, stimulating the production of desoxycorticosterone
Is there then more than one ACTH, or does this compound serve to stimulate
compound E and compound F as well as all the other compounds with similar
activity? The possibility of the presence of more than one ACTH has already
been proposed. With this in mind, if we view the adrenal in hypoadrenocorticism
as a "tired out" gland, unable to produce the correct or adequate
supply of hormones, being constantly bombarded by stimulatory influences
from above, we are in a better position to evaluate adrenal cortical extract
versus cortisone or ACTH therapy. If we give ACTH, we are, so to speak,
whipping a tired horse, getting a little extra cortisone to be sure, but
at what expense? If we give cortisone, we stop the bombarding of the gland
by tropic influences from above with respect to the cortisone only. What
about the tropic influences for the other steroids? Now, if we give adrenal
cortical extract, presumably we are supplying the adrenal steroids in the
same ratio to each other that they normally bear. Increased amounts of
these in the bloodstream would tend to shut off all tropic influences by
the general rule of endocrinologic action. If 10 cc. of adrenal cortical
extract are given intravenously, that is certainly not replacement therapy
(since the daily adrenal output is many times that amount), but at the
time of injection, blood circulating in the region of the pituitary contains
increased amounts of the whole circulating hormones. this shuts off all
pituitary tropic influences, not just ACTH for cortisone. The adrenal is
not under constant bombardment until the adrenal cortical extract is metabolized
in the liver or tissues. The inhibition is off the pituitary, and tropic
hormones are again release if the need arises. In the meantime the tired
adrenal has had a chance to rest and to build up its tone. At this time
another injection of adrenal cortical extract will suffice again to allow
it to regain more tone but will not entirely cause a cessation of activity,
as would large doses of cortisone, for the glucocorticoid portion.
Usually desoxycorticosterone acetate is not indicated in these cases.
There is most frequently a craving for salt, which is not harmful in itself
if given with adrenal cortical extract but this must be regulated when
the patient has received this mineralosteroid. Although desoxycorticosterone
acetate may improve the absorption of carbohydrates from the intestine,
it does not enhance gluconeogenesis during stress, and clinical results
have not warranted its general usage in hypoadrenocorticism.
An attempt has been made to condense and describe a vast syndrome which
has been recognized in a group of over 200 patients. Diagnosis is possible
by means of a careful endocrine history and physical examination, rather
than by elaborate laboratory tests. We have observed that hypoadrenocorticism
may result in fatigue, mental confusion, various arthritic pains, gastrointestinal
disorders, inability to concentrate, signs of disturbed carbohydrate metabolism,
etc. These patients respond to therapy which includes an autonomic stabilizer,
adrenal cortical extract injections, and an antihypoglycemic diet. The
rationale for adrenal cortical extract therapy has been discussed.
1. Natelson, S., Crawford, W.L., and Munsey, F. A.: Correlation of Clinical and Chemical Observations in the Immature Infant, Rockford Illinois, Munson Printing Co., 1952, p. 11.
2. Hartman, F. A., and Brownell, F.A.: The Adrenal Gland, Philadelphia, Lea & Febiger, 1949, p. 421.
3. Selye, H.: J. Clin. Endocrinol. 6: 153 (Feb) 1946.
4. Portis, S.A., Zitman, I.H., and Lawrence, C. H.: J.A.M.A. 144: 1162 (Dec.2) 1950.
5. Striker, C.: Illinois M.J. 102: 235 (Oct.) 1952.
6. Bercovitz, Z.T.: New York State J. Med. 53:2200 (Oct 1) 1953.
7. Tintera, J.W.: Unpublished data.
8. Tintera, J.W. and Lovell, H.W.: Geriatrics 4: 274 (Sept.-Oct.) 1949.
9. Lovell, H.W., and Tintera, J.W.: ibid. 6:1 (Jan-Feb.) 1951.
10. Idem: M. Times 80: 191 (Apr) 1952.
11. Webster, J.J.: Ann Int. Med. 38: 854 (Oct) 1950.
12. McGavack, T.H.: The Thyroid. St. Louis, C.V. Mosby, 1951.
13. Oleesky, S.: Lancet 1: 769 (Apr) 1953.
14. Albright, F.: Harvey Lect. 38: 152 (1943).
15. Selye, H.: Annual Report on Stress, Montreal, Canada, Acta, 1951, p. 217.
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