THE ADRENAL EXHAUSTION SYNDROME: AN ADRENAL DEFICIENCY

THE ADRENAL EXHAUSTION SYNDROME: AN ADRENAL DEFICIENCY *

F. G. Sulman, Y. Pfeifer, and E. Superstine

Bioclimatology Unit Department of Applied Pharmacology

Medical Center Hebrew University Jerusalem, Israel

The “exhaustion syndrome” was recognized by our group in 1969 as an adrenal medulla deficiency phenomenon. Further research showed that its detrimental effect is primarily due to adrenal medulla catecholamine deficiency; however, in most cases adrenal cortex hormones are also depleted, especially the androcorticosteroids ( 17-ketosteroids, 17-KS) and the glucocorticosteroids (17-hydroxysteroids, 17-OH).* This finding resulted from a study of urinary neurohormone excretion in persons exposed to permanent climatic heat stress. Such stress occurs mainly in tropic and subtropic regions where dry winds may blow during most parts of the year. It is, however, also common in countries where winds descend from high mountains, preserving their meteorological features of heat and dryness created by subsidence, which is defined as the slow downward motion of air panels over a large area usually combined with adiabatic (nonpermeable) warming up and drying of the subsiding air. As we have shown, people living in such an area suffer every year more and more from the effect of such winds, which create a state of permanent “perspiratio insensibilis.” This increased perspiration imposes heavy daily demands on the body’s catecholamine secretion, which protects the body from “oversweating” by contracting skin blood vessels. Moreover, it demands constant 17-OH secretion to compensate for sodium loss, which may lead to hyperpotassemia. The demand on stress hormones, especially 17-KS, results in a typical decrease of 17-KS secretion during heat stress, a fact that may be explained by an adrenal shift from androcorticosteroid to glucocorticosteroid production.

In temperate zones, adrenal exhaustion is less frequent because the climate provides cold days at random the whole year round. Still, the demands of daily stress and aging induce adrenal exhaustion fairly often.4

Some hot dry winds of ill repute are the Santa Ana of Southern California, the Arizona desert winds, the Melbourne Northern winds, the Argentine Zonda, the Sirocco of the Mediterranean, the Maltesian Xlokk, the Khamsin and Sharkiye of the Arab countries, the Sharav of the Old Testament haunting Israel, and the Foehn of Switzerland, Germany, and Austria. They are notori- ous for causing depression and fatigue, culminating in exhaustion (“tropical lethargy”). There are also complaints of irritation, such as headaches, irritability, and exacerbation of respiratory ailments due to serotonin overproduction.2 As the contradictory complaints of the millions of weather-sensitive patients do not allow proper diagnosis and treatment, we have differentiated the

* This work was supported by a grant from Mr. and Mrs. Herman Lane, New York.

918

Sulman et al.: Exhaustion Syndrome 919

complaints in 200 patients exposed to these winds by neurohormone urinalysis (TABLE 1).

In an earlier paper it was shown that in normal persons hot dry winds may cause increased sweat losses from 25% of the total fluid excretion under normal conditions, to up to 50%. The normal sodium chloride content of perspiration is 0.5%, so that the daily salt loss in the sweat may increase from 2 g to 4-5 g. This will naturally result in a smaller excretion of sodium in the urine and, in cases of dehydration, lead to a compensatory increased rate of potassium flow from the cells to the blood and urine. The flooding of the blood with potassium in extreme cases may explain the suffering and the typical ECG of cardiac patients from dry winds and the general adynarnia noted by healthy people. The sodium loss activates aldosterone and glucocorticosteroid production in the

TABLE 1

URINALYSIS OF 200 PATIENTS SUFFERING FROM HEAT %XESS. COMPARISON OF EXCRETIONS ON NORMAL DAYS AND HOT DAYS,

SHOWING TREND OF CHANGES

Excretion, per 24 hours

Parameters Studied Normal Days Heat Days

Epinephrine (pg) 1-4 0 -1 Norepinephrine (pg) 10-50 0-20 17-KS female (mg) 8-12 6-8

17-OH female (mg) 2-3 3-4 male (mg) 3-4 4-5

male (mg) 12-18 8-10

Serotonin (pg) 0-50 51-100 5-HIAA (mg) 1-6 7-25 Histamine female ( p g ) 15-90 90-150

male (clg) 20-65 65-130 Thyroxine (pg) 10-20 2 1-37 Na' (mEq) 60- 100 80-140 K' (mEq) 20-32 40-100 Creatinine (g) 1.5-2.5 3.0-4.0 Diuresis female (ml) 700-1,500 700-1,500

male (ml) 850-2,000 850-2,000

organism. Hence it is not surprising that 17-OH excretion rises on hot days. On the other hand, the chronic demand for catecholamines to prevent oversweating may induce an exhaustion of the adrenal medulla in patients exposed continually to subtropical or tropical heat (tropical lethargy). This phenomenon is the topic of the present paper, and in addition it will be shown that it is also the cause underlying staleness of long distance runners, a condition not appre- ciated until now.

PATIENTS AND METHODS

In order to obtain a random population of weather-sensitive patients, the Hebrew University and the Israel Broadcasting Service issued a release in which

920 Annals New York Academy of Sciences

people suffering from weather sensitivity were requested to apply to our Unit for proper examination and treatment. This appeal was answered at the, time by about 200 patients eager to participate in this research. Today thousands of patients are under our permanent supervision and are relieved of their sufferings by specific preventive treatments (TABLES 1-3). The heat-sensitive patients include young students, soldiers, adults, elderly people, smokers, nonsmokers, drivers, immigrants from temperate and from hot zones, and people of varied ethnic origin subsisting on different diets. Recently we added 30 long distance runners to our supervision in order to establish norms for their neurohormone requirements and the relation of such to proper performance.

TABLE 2

THREE TYPES OF REACTIONS TO HEAT STRESS REVEALED BY NEUROHORMONE ANALYSIS

1. Irritation syndrome (serotonin hy- Sleeplessness, irritability, tension, electrified perproduction). 43% of cases. Begins 1-2 days before arrival of heatwave because it is engendered by quickly moving air electricity.

hair, migraine, nausea, vomiting, sco- toma, amblyopia, tinnitus, anorexia, edemata, palpitations, precordial pain, dyspnoe, rheumatic pains, flushes with sweat or chills, vasomotor rhinitis, con- junctivitis, laryngitis, tracheitis, vertigo, tremor, hyperperistalsis, polyuria or polakisuria.

2. Adrenal exhaustion syndrome (adrenal deficiency). 44% of cases. Increases every year.

3. Intermittent hyperthyreosis. 13% of cases. Presents clinically a mixture of complaints listed in two types.

Hypotension, fatigue, apathy, exhaustion, depression, confusion, ataxia, adynamia, hypoglycemic spells.

Tachycardia, sleeplessness, irritability, tension, nausea, vomiting, palpitations, precordial pain, dyspnoe, sweat, tremor, abdominal pain, diarrhea, polyuria, al- lergic reactions, reddening of skin, acne, increased appetite, weight loss, overac- tivity, fatigue, exhaustion, depression, adynamia, confusion, anxiety, alopecia.

Urine Collection

Every patient had to undergo a general physical examination. If he was found to be a typical weather-sensitive person, he was given a note containing directions for collecting and despatching his urine, reading as follows:

“All urine excreted during 24 hours should be collected in a jar containing two teaspoonsful (10 ml) 3 N hydrochloric acid. This preserving fluid (marked poison!) must be put into the receptacle jar before starting urine collection. During collection of urine, the patient should avoid eating bananas, avocados, tomatoes, pineapples, and guavas. The following drugs should be avoided: reserpine, methyldopa, pressor amines, tricyclic antidepressants, and monoamine-oxidase-( MAO) -blockers. Urine samples should be sent to the Department in 200 ml bottles specifying name of patient, quantity excreted during 24 hours and date of collection.”

TAB

LE 3

RESU

LTS OF N

EUR

OH

OR

MO

NE

URINALYSIS I

N 20

0 PE

RSON

S SU

FFE

RIN

G F

RO

MH

EA

T S

TRES

S IN

R

EL

AT

ION

TO T

HE

IR C

LIN

ICA

L C

OM

PLA

INT

S O

N HOT

DA

YS,

COM

PAR

ED

W

ITH

NO

W D

AY

S*

TH

E Q

UA

NT

ITA

TIV

E

EVA

LUA

TIO

N

OF T

HE

CH

AN

GE

S F

OU

ND

BY

UR

INA

LY

SIS IS COMPILED IN T

AB

LE

1, EV

ERY

PATI

ENT

SER

VIN

G

AS HIS OW

N C

ON

TR

OL

*

Epi

neph

rine

, N

orep

inep

h-

17-K

S,

Sero

toni

n,

His

tam

ine,

So

dium

, Pe

rcen

tage

Group

Patie

nts

Synd

rom

e ri

ne

17-O

H

5-HIAA

T-4

po

tass

ium

of

cas

es

1 86

Ir

rita

tion

synd

rom

e 0

0 +

0 0

43 %

(s

erot

onin

hyp

er-

prod

uctio

n)

synd

rom

e (a

dren

al

defic

ienc

y)

reos

is

2 88

A

dren

al e

xhau

stio

n -

-

0 0

0 44%

3 26

Inte

rmitt

ent h

yper

thy-

+

+ +

+ +

13%

* +, in

crea

se; -, d

ecre

ase;

0,

no c

hang

e.

The

qua

ntita

tive

eval

uatio

n of

the

cha

nges

foun

d by

uri

naly

sis

is co

mpi

led

in T

AB

LE

1,

ev

ery

patie

nt serving as

his own

cont

rol.


The long distance runners included 30 students under supervision of our University Sport Laboratory, who were considered fit for long distance training after physical examination, lung capacity determination, electrocardiogram (ECG) , and blood pressure monitoring during exercise. These 30 students were asked to pass urine before and after running up to 5 km to allow a comparison between the pre-stress (ante) and the after-stress (post) neurohormone profile (TABLE 4). In these 30 students the only difference in urine collection was the immediate acidification of the urine after collection, the assay being evaluated per liter instead of per 24 hours’ excretion.

Urinalysis

The following urine examinations were carried out: epinephrine, norepinephrine, 17-KS, 17-OHS, serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), histamine, thyroxine, sodium, potassium, creatinine, and diuresis. Methods and results have been published by us.*,

Selection of Controls

The design of the study was double-blind throughout. Control values for neurohormone excretion of normal people are available in our Department from well over 1,000 persons. They show a daily epinephrine excretion of 1-4 pg/ day and norepinephrine excretion of 25-50 pg/day. Similar values pertain to persons whose catecholamines are assayed in single urines and evaporated per liter urine. The standard values for other neurohormones are presented in TABLE 1 . In the present study every weather-sensitive patient and every long distance runner had to serve as his own control. Urinalysis on normal days or before exercise yielded his normal neurohormone profile, whereas the changes due to heat or exercise were easily detected by comparison of the results of urinalyses. All figures were evaluated statistically by Student’s t-test ( p < 0.005). Completeness of urine collection was ascertained by the creatinine index in the 24 hours’ urine.

RESULTS

Weather-Sensitive Patients

Urinalysis (TABLE 1) and clinical symptomatology (TABLE 2) allowed the climatic heat syndrome to be split up into 3 different groups (TABLE 3 ) : “irritation syndrome” due to serotonin overproduction, 43% of cases; 7 “thyroid syndrome” due to intermittent hyperthyreosis, 13% of cases; “adrenal exhaustion syndrome,” 44% of cases.9 The evaluation of the neurohormone profile in long distance runners presented greater difficulties because of three other interferences described in TABLE 5 : influenza, dropping out before completing 5 km, and general lack of fitness.

Sulman et al. : Exhaustion Syndrome 923

Weather-sensitive patients may suffer from one or more of the following complaints of adrenal deficiency: hypotension, apathy, depression, fatigue, exhaustion, lack of concentration or confusion, ataxia or vertigo, and hypoglycemic spells, and they may also be prone to coronary insufficiency. The most typical complaint of this group is that its members suffer from climatic heat stress progressively more every year. This becomes especially evident in women, who react to it by chronic hypotension. We have shown in rats that the female is indeed more prone to heat stress exposure because of its lower level of andro- genic stress hormones.'O. l1

It is a well-known fact that weather-sensitive persons who have the chance of visiting a temperate climate during the hot periods of the year do not suffer from the typical progressive deficiency of adrenal activity, because there they encounter normal weather, which does not make any demands on their catecholamine, 17-KS, and 1 7 - 0 8 production. This gives them ample opportunity to restore the capacity of their adrenal gland. Urinalysis of such patients, at the brink of adrenal exhaustion, shows that they leave the tropics with sub- normal hormone excretion and return with normal levels.

Comparison of catecholamine excretion in weather-sensitive patients showed the following fluctuations in patients suffering from the exhaustion syndrome. Their epinephrine excretion amounts to approximately 1 &day on normal days and falls to 0-0.9 &day on hot days; norepinephrine ranges at 15-50 pg/day on normal days, and 1-10 pg/day on hot days. Statistical evaluation ( n = 200) yielded the following results:

before heat spell: 1 k 0.3 pg/day, p < 0.005; during heat spell: 0.4 f 0.1 pglday, p < 0.005; during heat spell on MA0 blocker treatment: 0.9 f 0.2 pglday, p < 0.005.

before heat spell: 32 f 5 &day, p < 0.005; during heat spell: 20 2 3 &day, p < 0.005; during heat spell with MA0 blocker treatment: 31 f 4 &day, p < 0.005.

Epinephrine, Mean Excretion k Standard Error ( S E ) :

Norepinephrine, Mean Excretion f SE:

The 17-KS and 17-OH values showed less typical results.

Long Distance Runners

Different types of neurohormone reactions were found in healthy long distance runners. Thirty male students 20-25 years old, training for a long distance contest, had their urinary neurohormone levels tested before and after running 5,000 m at an embient temperature of 10°-15" C. The first 25 runners to reach the tape showed the following typical pattern of reaction (TABLE 4 ) :

Stress Hormones, Average Decrease: 17-KS: from 12.0 to 8.0 mg/liter; 17-OH: from 3.8 to 2.5 mg/liter; 5-HIAA: from 5.4 to 3.5 mg/liter.

Fight and Flight Hormones, Average Increase: Epinephrine: from 0.7 to 3.6 &liter; Norepinephrine: from 22 to 41 &liter.

TABLE

4 \o

N

P

C

HA

NG

ES

OF

UW

AR

Y N

EU

RO

HO

RM

ON

E

LEVELS IN

30

MALE LONG D

IST

AN

CE

Ru

"Em

BEFORE

(ant

e) A

ND

AET

ER

(pos

t) EXERCISE

Epi

neph

- N

orep

inep

h-

Thy

roxi

ne

(pg/

liter

) (p

g/lit

er)

(mg/

liter

) (m

g/lit

er)

(mg/

liter

) (p

g/lit

er)

(pgl

liter

) A

ge Distance

rine

ri

ne

17-O

H

17-K

S 5-

HIA

A

His

tam

he

(km

)

E st

uden

t (yr)

(km

) 1

23

5 an

te

0.9

13.4

3.

2 10

.0

4.2

26

10

post

3.

7 36

.0

2.6

8.6

2.1

38

14

2 24

5

ante

0.

7 15

.8

3.1

10.0

5.

5 44

10

po

st

5.7

8.6

* 2.

7 11

.1 *

6.5

* 41

* 20

3

23

5 an

te

0.0

* 0.

0 *

3.6

20.5

3.

1 40

12

po

st

0.0

* 0.

0 *

3.2

10.5

0.

7 41

11

* 4

25

5 an

te

0.9

15.4

3.

4 18

.0

3.7

post

4.

0 41

.5

2.6

15.0

3.

0 80

20

5

23

5 an

te

0.4

10.8

3.

4 9.

5 4.

6 43

11

po

st

3.7

37.6

3.

0 6.

5 2.

8 6

25

5 an

te

0.3

37.3

4.

1 8.

0 3.

6 30

12

2.

7 38

.5

2.8

5.3

3.2

40

19

post

7

24

5 an

te

0.2

15.8

1.

7 7.

5 10

.0

41

13

Post

0.

8 57

.0

1.6

7.0

5.3

52

14

post

2.

4 35

.0

2.4

10.0

5.

1 51

14

9

21

5 an

te

1.2

14.1

3.

2 17

.6

8.4

32

8 po

st

3.5

28.3

2.

1 11

.9

7.6

57

13

10

22

5 an

te

0.2

24.2

1.

7 7.

0 4.

1 36

12

po

st

0.8

52.0

1 .o

6.

6 3.

8 58

24

11

21

3

ante

0.

3 24

.9

22.5

3.

2 2.

9 52

13

po

st

0.9

53.0

10

.5

2.6

1.7

53

14

12

22

2 an

te

0.4

20.1

21

.5

3.1

2.9

52

10

post

0.

8 42

.1

21.0

2.

8 1.

0 42

t 17

13

21

2

ante

1.

8 19

.7

22.0

2.

8 5.

8 30

8

post

3.

8 42

.0

12.0

2.

0 1.

7 49

10

14

23

2

ante

0.

4 18

.4

12.3

2.

1 2.

7 40

9

post

1.

8 59

.0

9.0

1.5

4.0

t 9

t

10

E z 37

11

d

67

16

?: 5 Q %

B

8 25

5

ante

1 .o

17

.8

3.1

13.0

7.

8 29

8

% z? 8' R Q Y

15

24

16

23

17

25

18

21

19

24

20

20

21

25

22

24

23

25

24

23

25

22

26

25

27

24

28

23

29

22

30

25

2 2.5

3.5

1

2 2 5 5 5 5 5 5 5 5 5 5

ante

0.3

po

st

1.6

ante

0.

4 po

st

1.7

ante

0.

5 po

st

2.3

ante

0.8

po

st

4.1

ante

0.7

ante

2.

1 po

st

0.3 t

an

te

0.4

post

3.

1 an

te

0.5

post

4.

1 an

te

0.9

Pat

3.8

an

te

0.8

post

0.

7 #

ante

0.9

po

st

4.1

ante

0.

3 Po

st

3.7

ante

0.

4 po

st

2.7

ante

0.8

po

st

1.6

ante

1.9

ante

0.

2 po

st

6.8

post

3.9

post

3.5

16.3

45

.3

10.3

29

.4

19.5

49

.3

44.3

75

.9

40.0

59

.9

19.7

43.7

10.1

24

.3

11.2

23

.4

13.4

36

.0

15.8

15.4

41

.6

10.8

36

.6

37.3

38

.6

15.8

57

.6

17.9

35

.6

24.0

52

.1

9.7 #

12.5

13

.0 t

18

.5

12.0

19

.0

10.5

10

.0

7.6

11.0

9.

5 19

.0

14.0

12

.0

15.5

t

14.3

11

.4

10.0

8.

7 10

.1

11.1

#

18.0

15

.1

9.5

10.5

#

8.0

5.3

7.5

7.1 3.1

2.4

7.0

6.6

3.8

3.1

4.8

4.0 3.1

2.2

2.4

1.8

3 .O

2.6

3.1

3 .O

3.4

3.6

t 2.9

2.

0 3.

2 2.5

3.1

3.7 #

3.

4 2.7

3.

4 3.

1 4.

1 2.8

1.

7 1.6

4.1

2.4

1.7

1 .o

8.0

10.0

t

6.1

8.1

t 3.8

2.

1 4.

5 6.9

t

3.2 1.8

4.5

2.3 4.5

2.3

4.1 2.1

4.2 2.3

6.5

7.6

# 3.6

3 .

O 4.

7 4.9

#

3.6

3.2

10.0

5.3

7.

8 5.

1 4.2

3.

6

40

41

34

44

28

40

31

39

41

64

38

37

71

93

36

38

27

38

43

40 #

37

70

43

57

30

41

42

52

29

51

36

58

12

10 t

10

25 8 10

9 17

11

18

m

10

E 9

t

14

E E n 19

17

19

10

14

20

12

# 11

21

11

17

12

19

13

8 14

11

22

> .. b. 8 E. a

17

8 m

r

* Ano

mal

ous f

indi

ng ca

used

by

influ

enza

infe

ctio

n.

t Ano

mal

ous f

indi

ng, s

tude

nt d

id n

ot c

ompl

ete

5 km.

rg

tu ul 2

Ano

mal

ous f

indi

ng, s

tude

nt was u

nfit.


Metabolic Hormones, Average Increase: T-4 (urinary) : from 10 to 15 pg/liter; Histamine: from 30 to 42 pg/liter.

All changes were highly significant by Student's t-test.

THERAPY

Weather-sensitive patients can be treated at any time. Long-distance runners, however, can only be treated during their period of training, otherwise such treatment would be considered as illegal doping.

Treatment should consist of minidoses of monoamine oxidase blockers (MA0 inhibitors). They allow better use of the adrenal catecholamine reserves and recuperation of the exhausted adrenal medulla. The efficacy of M A 0 inhibitor use is always based on an extremely low dosage, since we are dealing, essentially, with healthy persons without any psychogenic anamnesis or diagnosis. We start the patient on '/4 of a tablet (e.g., 2.5 mg isocarboxazid per day) of one of the accepted M A 0 blockers (FIGURE 1 ) . Only rarely does the dosage have to be increased to %-1 tablet per day, but never more. Placebos are used in every case, as they allow us to arrive at an unequivocal appraisal of the patient's requirements. Evaluation is facilitated by repeated neurohormone assays and use of special forms which the patient completes after taking the drug for a brief period.

After a long search for a M A 0 blocker with an immediate effect, we selected as the drug of choice, isocarboxazid (Marplan, Roche, FIGURE 1 ) . This prep- aration is a M A 0 blocker which, without causing any excitement or tension in the patient as other M A 0 blockers or pressor amines are apt to do, brings about an elated mood within one hour, which completely changes the mental outlook of the patient. It is sufficient to give the patient %-% tablet (2.5-5 mg) in the mornings to induce full work capacity. This treatment will normalize catecholamine production within 7 days (urine epinephrine rising from below 0.1 pg to 1-4 pglday) without, however, unduly increasing the level of other biogenic amines, such as serotonin. Administration of ACTH is not necessary as 17-KS and 17-OH levels will automatically rise during treatment with M A 0 blockers. It is clear that protracted treatment with M A 0 blockers would be detrimental to the adrenal medulla, and could also precipitate the well-known hazards that every patient encounters when he takes M A 0 blockers for a pro- longed time and inadvertently adds tyramine to his food intake by consuming cheese, beer, wine, or pressor amines.

The results of treatment were especially rewarding with regard to hypotension, which reverted to normal values, blood pressure, if low, rising by 10-20 mmHg. Ataxia or vertigo due to hypotension disappeared. Subjective complaints, such as fatigue, apathy, exhaustion, depression, confusion, and hypoglycemic spells were no longer reported. In nearly all cases the patients who were previously unable to pursue their work could now perform their duties without any difficulty and started to resume sport exercises as, e.g., long distance running.

Side reactions of the isocarboxazid therapy were very rare. They consisted mainly of sleeplessness and restlessness. These complaints disappeared when the patients were advised to take not more than '/4 dose of an M A 0 blocker


MOM0 - AWINE HORMONES I

1 W R . A D R E N A l l ~ M o - 0 - n - cn,-m~(, YO' s w

2 ADRENALINC n;og-c:- cn,--wncw,

3 SEROTONIN n a - q -ccn,-cn,--wn,

7. TRANVLCVPROMINE IParnata 1

11. PAR V I N I&

11 lPROCCO2 I05 Ilurrum)

It3 - co- MY- MY-C%

Q -cn,-Mn-co-Cn,

Q -cn,--wn-yn

C&-c'o

Q-y-w-mn, CHI

Q - CM, - - C$-C .CM Cw,

CI- Q - ocn,-co--Wn icn,)z- cn-wn

FIGURE 1. Syngps; ' of MAO-blockers and their mechanism of action by fitting into the receptor for catecholamines norepinethrine ( 1) and epinethrine (2) and serotonin ( 3 ) . Compounds 7, 9, 10, and 11 are currently in use; compounds 4, 5, 6, and 8 have been withdrawn from the market. Compounds 7, 9, and 10 have an immediate effect, beginning 30-60 min after intake and lasting for 6-8 hours. Compound 12 is rarely used.


after breakfast. It is interesting to note that in this group there were also patients who preferred additional treatment with xanthine derivatives, such as caffeine, euphylline nicotinate (Hesotin), or xanthinone niacinate (Complamin) . It is well known that such preparations mimic the action of catecholamines at the cyclic-3',5'-AMP level. Amphetamine and its congeners are contraindicated since they force the debilitated adrenal medulla into complete atrophy and inactivity. Moreover they tend to produce addiction and, sometimes, psychosis.

DISCUSSION

The different trends of catecholamine excretion in weather-sensitive patients and long distance runners are a most challenging finding because they show the difference between newcomers and veteran residents in the subtropics and tropics. As hot dry weather brings about passive dilation of the peripheral blood vessels and augments perspiration, catecholamine secretion becomes increased in order to contract the vessels and prevent excessive perspiration. This reaction is in contradistinction to the common view that wet heat may inhibit epinephrine secretion. Urinalysis clearly reveals hyposecretion of catecholamines as the cause of tropical lethargy.

Urinalysis also reveals that MAO-blocker treatment can restore the depleted epinephrine, norepinephrine, 17-KS, and 17-OH levels to normal values without affecting serotonin production. This finding would rule out the suspicion that tropical lethargy, i.e., lack of exercise is the cause of low urinary catecholamines.

In long distance runners catecholamine excretion increases considerably after exercise, and if it does not, the cause for it should be investigated (TABLE 4).

Perusal of TABLE 4 allows the following conclusions: Students 2 and 3 suffered from influenza on the day of exercise, yet because of insignificant fever reaction they were admitted to the 5-km training. The paradoxical reaction of their neurohormones is marked by an asterisk. Students 12, 14, 15, 16, 18, 20 dropped out after 1-2.5 km, probably because their neurohormone profile could not cope with the demands of a 5-km run. Students 21 and 24 were considered not fit for long-distance running, while No. 26 was regarded as not too severely hampered. When the tests were repeated, our assumption proved to be correct and the students 21 and 24 reverted to short-distance running,

' whereas student 26 was doing well on 5-km distance running after brief treatment with a MA0 blocker.

Our findings do not necessarily imply that treatment with M A 0 blockers increases adrenal medulla output. It can, however, be assumed that better use of catecholamines, due to MA0 blocker, allows the adrenal medulla to re- cuperate, an effect obtainable also by sending a patient for some months to a moderate climate. In any case the patients who had undergone the MA0 blocker treatment with minidoses for 1-2 months were usually immune to heat-fatigue or long-distance-running staleness for a full year at least.

The beneficial effect of an MA0 blocker like isocarboxazid on the adrenal medulla exhaustion syndrome finds its experimental backing in the observation by Randall and Bagdon (1959) who showed that the duration of its action in vivo may be as long as 20 days after a single dose.12

It is tempting to look for a teleological explanation of the typical pattern of neurohormone reactions in long distance runners. We have given pertinent


interpretations to the typical changes encountered, which are compiled in TABLE 5.

SUMMARY

We have observed that people when exposed to extreme heat stress can suffer from depletion of epinephrine, norepinephrine, and adrenal corticosteroids. This was proven by daily urinalysis. Having ascertained that they were suffering especially from lack of monoamines, we found in them all the symp- toms of catecholamine deficiency, i.e., hypotension, fatigue, exhaustion, apathy, depression, lack of concentration, confusion, hypoglycemic spells, and ataxia.

TABLE 5

MOOTED MECHANISMS OF NEUROHORMONE REACTIONS IN LONO DISTANCE RUNNERS

Hormone Function Reaction Explanation ~~

17-KS

17-OH

5-HIAA

Androgen metabolite Decrease Physical ability to cope with stress

Cortisone metabolite Decrease Mobilization of sugar and sodium

Serotonin metabolite Decrease Mental ability to cope with stress

Norepinephrine Fight hormone Increase Improves circulation and mobilizes sugar

Epinephrine

Thyroxine Histamine

Flight hormone Increase Improves heart action, circulation and sugar metabolism

Metabolic hormones Increase Required for increased metabolism and heat production

The most typical complaint of such patients is that they suffer progressively more each year from “aging,” exertion, or stress. Sport does not help them.

During heat spells or extreme effort, people have to secrete more catecholamines to cope with the demand and to contract their skin vessels in order to avoid excessive sweating. This repeated stress can induce adrenal medulla exhaustion with particularly low values of epinephrine. Norepinephrine follows suit, but it never reaches zero level (as epinephrine does) because of the extra adrenal production of norepinephrine as a sympathetic transmitter. The urinary excretion of 17-KS and 17-OH becomes sometimes reduced too.

Different results were obtained in long distance runners. Thirty male students, 20-25 years old, training for a long distance contest, had their urinary neurohormone levels tested before and after running 5,000 m at an ambient


temperature of 10"-15" C. The runners to reach the tape showed decreases in the stress hormones 17-KS, 17-OH, and 5-HIAA; increases in the fight hormones epinephrine and norepinephrine; and increases in the metabolic hormones T-4 (urinary) and histamine. All changes were highly significant.

We have now been treating such patients for 10 years with minidoses of MA0 blockers (1-10 mg/day). A low dosage of %-I tablet/day completely cures the patients of their disability and adynamia, without any danger of a cheese tyramine reaction. Not every M A 0 blocker is suitable for this treatment: it has to be one with an immediate effect. We have singled out in particular the following preparations that produce relief within 30 minutes without producing any tolerance or addiction: isocarboxazid (Marplan, Roche) and mebanazine (Actomol, ICI) . Replacement of the corticosteroids by anabolic hormones is rarely required.

REFERENCES

1. WELLER, C. P. & F. G. SUN. 1969. Effect of climatic heat stress on catecholamine excretion. Biometeorology (Suppl. to Int. J. Biometeorol.) 4(Pt. 11): 30.

2. SULMAN, F. G., A. DANON, Y. PFEIFER, E. TAL & C. P. WELLER. 1970. Urinaly- sis of patients suffering from climatic heat stress (Sharav). Internat. J. Biome- teorol. 14: 45-53.

3. SULMAN, F. G. 1976. Health, Weather, Climate. Karger Publications. Basel, Switzerland.

4. SULMAN, F. G. & E. SUPERSTINE. 1972. Aging and adrenal medulla exhaustion due to lack of monoamines and raised monoamine-oxidase levels. Lancet U: 663.

5. SULMAN, F. G., N. HIRSCHMAN & Y. PFEIFER. 1964. Effect of hot, dry, desert winds (Sirocco, Sharav, Hamsin) on the metabolism of hormones and min- erals. Proc. Lucknow Symposium on Arid Zones UNESCO : 89-95.

6. TAL, E. & F. G. SULMAN. 1972. Urinary thyroxine test. Lancet i: 1291. 7. DANON, A. & F. G. SULMAN. 1969. Ionizing effect of winds of ill repute on sero-

tonin metabolism. Biometeorology (Suppl. to Int. J. Biometeorol.) 4(Pt. 11):

8. SULMAN, F. G., E. TAL, Y. PFEIFER & E. SUPERSTINE. 1975. Intermittent hyperthyreosis-A heat stress syndrome. Hormones Metabol. Res. 7: 424428.

9. SULMAN, F. G., Y. PFEIFER & E. SUPERSTINE. 1973. Adrenal medullary exhaustion from tropical winds and its management. Isr. J. Med. Sci. 8: 1022-1027.

10. KOCH, Y., Y. PFEIFER & F. G. SULMAN. 1969. Effect of climatic heat stress on the development of rats, Int. J. Biometeorol. 13: 93.

11. WELLER, C. P., S. DIKSTEIN & F. G. SULMAN. 1969. The effect of heat stress on body development in rats. Biometeorology (Suppl. to Int. J. Biometeorol.) 4(Pt. 11): 29.

12. RANDALL, L. 0. & R. F. BAGDON. 1959. Pharmacology of isocarboxazid and other amine oxidase inhibitors. Ann. N.Y. Acad. Sci. 80: 626-642.

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THE ADRENAL EXHAUSTION SYNDROME: AN ADRENAL DEFICIENCY