THE EFFECT OF ACTH AND CORTISONE ON CEREBRAL BLOOD FLOW AND METABOLISM

THE EFFECT OF ACTH AND CORTISONE ON

CEREBRAL BLOOD FLOW AND METABOLISM

Willis Sensenbach, … , Leonard Madison, Lamar Ochs

J Clin Invest. 1953;32(4):372-380. https://doi.org/10.1172/JCI102748.

Research Article

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FLOW 'AND METABOLISM1

By WILLIS SENSENBACH, LEONARD MADISON, AND LAMAR OCHS (From the Departmentof Internal Medicine of the Southwestern Medical School of the

Uni-versityof Texas, Dallas, and the MedicalServieofthe VeteransAdministration

Hospital,Dallas, Texas)

(Submitted for -publication October 24, 1952; accepted December 31, 1952)

Mental aberrations of varioustypesandin vary-ing degree are observed in many patients durvary-ing the administration ofACTH or cortisone. Most

oftenthe changesare those of personality or mood; restlessness, irritability, insomnia, elation,

depres-sion, euphoria are among the more common mani-festations. Less commonly, but nonetheless, not rarely, frankly psychotic episodes occur. In

Cushing's syndrome, where there is an abundance ofendogenous adrenalcortical hormones, there is a

high incidence of abnormal mentation including

hysteria,. suicidal depressive states, simple schizo-' phrenia -and paranoia (1). The production of mental symptoms and psychoses consequent to the

administration of ACIH or cortisone and their frequency in Cushing's syndrome suggest the

pos-sibility that there is abiochemical basis for certain of thepsychoses and personality disorders.

This report deals with the study of the cerebral circulation and metabolism before, during, and after the administration of ACTH and cortisone

for.thepurpose of determining the cerebral

hemo-dynamic and metabolic effects of these hormones

and possibly of elucidating the relationship of the

physiological derangements to the -induced mental aberrations.

METHOD

The cerebralblood flow (CBF) was determined by the nitrous oxide method of Kety and Schmidt (2) as modi-fied by Scheinberg and Stead (3) except in the case of T.B.C. where the original method (2) was employed.

Thecerebral oxygen consumption (CMRog) andcerebral glucoseconsumption (CMRglu) were calculated from the CBFandthe arterio-cerebral venous oxygen and glucose differences. The cerebralvascular resistance (CVR) was

calculated from the CBF and the mean arterial blood

1Reviewedin_{the VeteransAdministrationand published}

with the approval of the Chief Medical Director. The statements and conclusions published by the authors are

theresultof their own study and do not necessarily reflect

the opinion or policy of the Veterans Administration.

pressure which was measured directly from a peripheral artery, usually the femoral, with a damped mercury

ma-nometer. Arterial and cerebral venous blood samples were drawn simultaneously just before each blood flow

procedure. Blood oxygen and carbon dioxide content

were determined manometrically (2). Blood sugar was

determined by Nelson's modification of the Somogyi method (4).

Complete studies of cerebral hemodynamics and metab-olism were undertaken on 45 occasions in 12 patients in

the ACTH2 group. These comprised pretreatment

de-terminations in 11 ofthe 12 patients;from one to six

de-terminations on each patient during the time they were

receiving 10 mgms. to 200 mgms. of ACTH daily; and

in many instances, as a further control, studies were

re-peated 10 to20 days after cessation of hormone therapy. The observations during the treatment period in 9 of

the 12 patients inthe ACTHgroupwereperformed after

thepatientshad received thedrugfortwotothree weeks. In three instances (E.R.S., L.R.C., and J.R.B.),

long-term studies extending from three to eight months were

performed, during which time repeated observations

were made. The data obtained from 2 patients with

Cushing's syndrome are also included.

Thirty-two studies were performed on a second group of 9 patients who received cortisone in doses ranging

from 100 to 200 mgms. daily. Pretreatment, treatment, and post-treatment studies were performed on at least

one occasion in each patient at about the same time

in-tervalsasthose in theACTH group.

The data wereanalyzed statistically by the method of paired observations; the pertinent difference between

val-ues obtained before andduringadministration ofthe

hor-mone were calculated for each subject. The mean of

those differences together with its standard error was then calculatedfrom the individual differences. P values

so determined are recorded in Tables I to IV. Where multiple studies on one patient were done, the values were averaged and this average was used in thecalculation of individual differences, standard deviation and standard

error.

RESULTS

Cortisone. The results of studies made before, during and after the administration of cortisone

2Weare indebtedto Dr.JohnR. Moteof the Armour Laboratories, Chicago, Illinois, for making available the ACTH used in these studies.

EFFECT OF ACTH AND CORTISONE ON CEREBRAL BLOOD FLOW 373

TABLE I

Theeffectofcortisoneoncerebral hemodynamicandmetabolic

functions

Cerebralblood Cerebral vascular Mean arterial Cerebral metabolic Cerebral metabolic

Daily How (CBF) resistance(CVR) bloodpressure rateoxygen rateglucose dose _cc./mi.1.100gins. mm.Hg1cc./mi*.f (MABP) (CMRo2) (CMRglu)

Subject Diagnosis Age Corti-sone_{sone --_____}mm.Hg c.1min./Ogis. mgms./min./100gis.

mgm.,./

day Pre Treat- Post- re _{Treat- Pot Pr-Treat-} Post- Pre- Treat- Pot Pr-Treat- POSt-t|reat-_metmentmen treat_mentmamettreat- _Ttreat- treat- _{ment treat-} treat- t

treat-ment men tetment ment ment ment ment et ment

T. B.C. Rheumatoid 38 100 51 44 54 1.35 1.79 1.27 68 79 69 2.91 2.68 3.38 arthritis

L. N. W. Rheumatoid 26 100 76 67 78 1.00 1.08 0.98 76 73 77 4.13 4.14 4.36 3.80 7.37 8.58 arthritis

R. H. H. Periarteritis 33 100 59 66 43 1.23 1.22 1.60 73 81 69 3.75 4.74 2.73 5.31 8.58 3.87

nodosa 200 74 1.21 90 4.82 5.92

(70)* (1.22) (86) (4.78) (7.25)

H.G. Ulcerative 26 100 58 46 55 1.27 1.39 1.05 74 64 S8 2.61 2.61 3.12 5.22 3.22 S.50 colitis

D.L.G. Dermatitis 32 200 53 53 52 1.35 1.39 1.36 72 74 71 4.12 4.00 4.10 5.83 4.77 3.64

D. S. Rheumatoid 28 200 57 54 53 1.26 1.35 1.32 72 73 70 3.32 3.27 3.20 3.99 4.86 4.24 arthritis

C. A. Silicosis 53 100 49 54 45 1.85 2.00 2.11 91 108 95 3.18 3.56 3.55 5.16 3.60

43 2.58 III 3.14

_ (49) (2.29) (110) (3.35)

R.G. Scleroderma 57 100 70 73 45 1.21 1.59 2.07 8S 116 93 3.77 4.54 3.04 4.20 2.92 5853

51 1.53 78 3.73 1.53

(48) (1.80) (86) (3.39) (3.64)

T.J. L. Eczematoid 58 100 110 114 68 0.66 0.78 1.13 73 90 77 4.3S 4.45 2.60 11.0 5.70 3.40

dermatitis 200 58 88 1.48 0.75 86 66 2.92 3.S6 4.64 5.28

(86) (78) (1.13) (0.94) (88) (72) (3.69) (3.03) (5.17) (4.34)

Mean 64.7 60.2 56.2 1.24 1.47 1.38 76 84.8 74.1 3.57 3.67 3.43 5.62 5.09 4.68

S.D. 18.0 13.6 12.3 .30 .11 .37 6.9 16.6 10.5 .56 .76 .51 2.31 1.50 1.58 S.E. 6.4 4.8 4.3 .10 .04 .13 2.4 2.8 3.3 .20 .27 .16 .94 .57 .60

PValue >0.2 <.01 <.05 >0.5 >0.5

*Values inparenthesesare

averages

for themultipledetermination listed.

to nine

subjects

are

_presented

in Table I andTable II. There were

significant

increases in the mean CVR from 1.24 to 1.47 mm.

Hg

per cc. per min. per 100 gms.

(P

= _<

_.01),

and MABP from 76

to 84.8 mm.

Hg

(P

= <

.05) during cortisone

therapy.

However,

consequent to a

_parallel

in-crease in both these

values,

no

change

inCBF

oc-curred

(P

= _>

_.2).

Neither the increase in

CMRo,

from 3.57 to 3.67 cc. per min-. per 100 gms. (P = >

.5),

nor the

changes

observed in the

CMRglu (P

= _>

_.5)

were

significant.

ACTH.

The data obtained from studies made before,

during,

and after the administration of ACTH to 12

subjects

are

presented

in Tables III and IV. The mean CBF was unaltered

during

ACTH therapy

(P

= _>

_.5).

The increase in MABP

(77.2

to 85.3 mm.

Hg)

is

highly

signifi-cant

(P

= _< .001); the

changes

in mean CVR

(1.29 mm.

Hg

per cc. per

min.

per 100 gms. to

1.59 mm. Hg per cc. per min. per 100

gms.)

(P

= _>

_.05),

mean

CMRo, (3.69

cc. _{per min.}

per 100 gms. to 3.96 cc. per min. per 100

gms.)

(P

= _>

_.3),

_and mean

CMRglu

(5.48

mgms. per min. per 100 gms. to 5.25 mgms. per min. per 100

gms.)

(P

= _>

_.7)

_arenot.

_Although

_{the 23 per} cent increase in mean CVRis not

statistically

sig-nificant,

it is to be noted that it returned to its pretreatment control value after ACTH was

dis-continued.

Mean cerebralvenous

02

contentdecreased

sig-nificantly

from 10.39vol. per cent to 9.12 vol.per

cent

(P

= _<

_.01)

_and cerebral venous CO2

con-tentincreased from

53.44

vol. percentto56.81 vol.

per cent

(P

= _<

_.05).

No other

significant

changes

in arterial or cerebral venous blood

con-stituentsoccurred.

The

effect of prolonged

administration

of

ACTH.

In the cortisone series and in mostof the

_subjects

in the ACTH series the

drugs

were administered as a constant dose for

relatively

short

_periods,

usually

two to three weeks. In the three

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EFFECT OF ACTH AND CORTISONE ON CEREBRAL BLOOD FLOW 375

TABLE III

The effect of A CTHoncerebralhemodynamic and metabolicfunctions

Cerebralblood Cerebralvascular Mean arterial Cerebral metabolic Cerebralmetabolic flow(CBF) resistance(CVR) bloodpressure rate oxygen rateglucose Daily cc./ms.ilooz mm.Hg/cc./min./ (MABP) (CMRos) (CMRglu)

Sujc100gMs. mm.Hg cc.Imix.I100gms. mgms./min./100gm$. Subject Diagnosis Ae ACTH

,.g/n1.-da Pre- _Tret- Post- Pre- _{Tret -Tet-}Post- Pre _ra-Post- Pre- e _rat

Post-treat- _meat treat- treat- meat tt- trea eat- treat- treat-Teat r Treat-

treat-meat metmeat meat mentmeamett meat ment meat

H. A. B. Rheumatoid 41 100 54 63 48 1.43 1.33 1.68 77 84 79 3.31 3.63 2.64 4.86 2.50

arthritis 200 73 1.17 86 3.94 7.30

(68)* (1.25) (85) (3.79) (4.90)

J. J. N. Rheumatoid 25 100 67 S2 68 1.19 1.62 1.12 80 84 76 4.69 3.97 4.01 8.71 5.72 7.48

arthritis 200 79 1.17 93 6.01

(66) (1.40) (89) (4.99)

W. F.G. Ulcerative 46 100 49 56 1.46 1.42 69 80 3.51 3.63 6.S8 3.92

colitis 100 65 1.26 82 3.46 S.85

(61) (1.34) (81) (3.5S) (4.89)

H. H. Bronchial 26 100 47 62 1.57 1.01 74 63 4.63 4.34 6.58 asthma

R.H. H. Rheumatoid 23 100 62 61 1.16 1.45 72 89 3.81 4.94 3.05 arthritis

H.G. Ulcerative 25 100 58 36 55 1.27 1.97 1.05 74 71 58 2.61 2.16 3.12 5.22 1.80 5.50 colitis

D.L. G. Dermatitis 31 100 53 53 52 1.35 1.66 1.36 72 88 71 4.12 4.11 4.10 5.83 5.83 3.64

A.L. D. Dermatitis 42 100 66 25 85 1.05 3.04 0.73 69 76 62 3.50 1.69 3.83 5.28 3.00 4.25

E. R. S. Rheumatoid 30 120 76 77 1.08 1.01 82 78 4.16 4.65 5.32 3.08

arthritis 80 76 1.08 82 4.29 5.32

20 70 1.20 84 5.10

160 84 1.05 88 5.17 10.10

20 56 1.52 85 3.46 3.36

(73) (1.17) (83) (4.53) (5.47)

J. R. B. Rheumatoid 29 120 59 80 1.33 1.06 79 85 3.99 4.38 3.54

arthritis 80 82 1.01 83 6.15 9.02

160 S0 1.70 85 4.07 6.50

120 41 2.14 88 3.41 5.74

80 71 1.18 84 5.10 6.39

80 60 1.30 78 3.80 4.20

(64) (1.40) (84) (4.49) (6.37)

L. R.C. Rheumatoid 36 160 69 65 1.09 1.29 75 84 3.46 3.77 2.07 3.25

arthritis 120 75 1.17 88 4.96 7.50

10 75 0.89 75 4.29

160 63 1.37 86 3.64 6.30

160 S1 1.74 89 3.96 5.10

(66) (1.27) (84) (4.12) (5.54)

L.A. E. Bronchial 100 57 75 1.75 1.59 100 119 3.43 4.49 7.40 9.00

asthma

Mean 111 60.9 57.9 61.7 1.29 1.59 1.16 77.2 85.3 68.2 3.69 3.96 3.67 5.48 5.25 5.22

S.D. 7.6 15.1 12.3 .61 .50 .30 8.3 11.6 7.7 .52 1.08 .60 1.77 1.70 1.47 S.E. 3.2 4.4 5.5 .19 .15 .13 2.6 3.5 3.5 .17 .33 .30 .59 .57 .85

PValue >0.5 >.05 <.001 >0.3 >0.7

*_Valuesinparenthesesareaverages for themultipledetermination listed.

ministered in varying amounts during a three to eight monthperiod of time. The dosage schedule, duration of treatment, and the results of repeated

measurements ofcerebral hemodynamic and meta-bolic functions in these subjects are presented in Table V. It can be seen that there is a wide varia-tion in all funcvaria-tions during the extended adminis-tration of ACTH. No apparent relationship ex-ists between these variations and (a) duration of treatment, (b) size of the daily dosage of ACTH,

or (c) changes in the arterial and cerebral venous

blood constituents. There is no evidence to sug-gest that they were related to

changes

in the clinical status of the disease for which the

patients

were being treated.

Cushing's syndrome. Data on the cerebral cir-culation have been obtained from two

patients

suffering from advanced

Cushing's

syndrome

(Table VI), associated with bilateral adrenal

hy-perplasia. The first

patient,

B. L.

G.,

was

un-treated when the studies were done. There is a

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EFFECT OF ACTH AND CORTISONE ON CEREBRAL BLOOD FLOW

TABLE V

Cerebral hemodynamic and metabolic funtions in three subjcts to whom A CTH wasadministeredcontinuously in varyingamounts overperiods of from three to eight months

Subject Age Dise

J. R. B. 29 Rheumatoid

arthritis

Mgms. of

ACTH/24 hours being administered attimestudies

weremade 0 120 80 160 120 80 80 Durationof treatment in days at time studies were made 0 6 36 72 101 155 245 CBF cc./min./ 100gms. 59 80 82 50 41 71 60 CVR mm.Hg/cc./ mis./100gms. 1.33 1.06 1.01 1.70 2.14 1.18 1.30 MABP mm.Hg 79 85 83 85 88 84 78 CMROs cc./min./ 100gms. 3.99 4.38 6.15 4.07 3.41 5.10 3.80 CMRglu mgms./min.I 100gms. 3.54 9.02 6.50 5.74 6.39 4.20

E.R.S. 30 FRheumatoid 0

arthritis 120

80 20 160 20

L.R.C. 36 Rheumatoid 0

arthritis 160 120

10

160 160

0 76 1.08

4 77 1.01

33 76 1.08

69 70 1.20

84 84 1.05

147 56 1.52

0 69 1.09

6 65 1.29

16 75 1.17

57 75 0.89

65 63 1.37

86 51 1.74

82 4.16 78 4.65 82 4.29 84 5.1& 88 5.17 85 3.46 75 3.46 84 3.77 88 4.96 75 4.29 86 3.64-89 3.96

cc.per min. per 100gms.) and MABP (137 mm.

Hg). CBF (67 cc. per min. per 100 gms.),

CMRo,

(4.13 cc. per min. per 100 gms.), and

CMRglu (5.36mgms. permin. per 100gms.) are

wellwithin normal limits. In the second patient, F. V. B., the studies were made after the institu-tion of an intensive and generally satisfactory program of treatment which included irradiation of thepituitary gland, sodium restriction, and the administration of supplementary potassium. The

bloodpressure hadreturnedtonearnormallevels,

the edema had been controlled, and the metabolic alkalosis corrected at the time the studies were

made. The CVR (1.59 mm. Hgpercc. per mnin. per 100 gms.) and MABP (92 mm. Hg) are

slightly increased above the mean values for

nor-mal men of this age group. Cerebral blood flow

(58 cc.per min.per 100gms.), CMRo, (4.12 cc.

permin.per100gms.),and CMRglu (6.38mgms.

per min. per 100 gms.) are well within normal

limits.

DISCUSSION

Aconsideration of themean values of the func-tions measured in these two groups of patients shows that the CBF isnotalteredby the

adminis-tration of cortisone or ACTH. These results are

similar to those of Alman and Fazekas (5), who

found no changes in cerebral hemodynamics or

metabolism inasmallgroupofpatients during the

first threetofour days of administration of ACTH. Schieve, Scheinberg, and Wilson (6), however, in

a larger series of patients, treated over a longer

period of time, a study more comparable to the

presentone, found a significant decrease in CBF

during the administration of ACTH. This was a consequence of a marked increase in calculated mean CVR. Their findings suggest that the

in-crease in vascular resistance that has occurred in

the brain is ofgreater magnitude than that of the body as a whole. The findings of this study, on

the other hand, would indicate that the increase incerebral vasculartonethatmayoccurduring the

administration of ACTH and cortisone is simply

a reflection of the increase in total peripheral

re-sistance. Hemodynamically,thechangesare

iden-tical to those known to exist in essential hyper-tension, i.e., parallel increases in MABP and

CVR; normal CBF (7). The increases in mean

arterial and cerebral venous CO2 content

ob-served during treatment with both cortisone and

ACTH are slight and arenot statistically

signifi-cantexceptinthecaseof the cerebralvenousblood

in the ACTH-series. Nevertheless, they may

0

e4

.,,flect

the presence of a mild metabolic alkalosis in these

_{subjects. Unfortunately,}

ourdata on blood

I

6

- pH are

inadequate

to substantiate this

point.

The

small reduction in mean arterial and cerebral

ve-nousblood sugar that occurred

during

the

adminis-cokR

0

tration of both cortisone and ACTH may have been a consequence of increased insulin

produc-tion or decreased

production

-of

growth

hormone,

LKg;

o b or both

(8-11).

;

_r

6 A consideration of individual subjects in both

the cortisone and ACTH treated series reveals an occasional instance in which a striking reduction

in CBF occurred during the administration of the

< _{IX o ^ drug, with return to its control value after}

treat-ment was discontinued. (H. G. and A. L. D. in

3

llalx$|the ACTH series and T. J. L. in the cortisone se-IV; > _{ries.) The remainder of the cases fall in general}

into two _groups:

_(a)

those in whom a

parallel

rise in MABP and CVR occurred without a change inCBF

_and;

_(b)

thosein whomthe CVRwas

un-changed, with variations in CBF apparently

de-pendent

upon

changes

in MABP.

In those

_patients

studied

_repeatedly

_during

the

long continued administration of ACTH, no changes in cerebral hemodynamics or metabolism wereobserved that could be attributed to thedrug,

the size of the

_dosage

or

duration

of

administration.

8j The data

provide

no clear

explanation

for the

6 ¢t 0c cause of the increase in CVR observed in the

ma-jority

of

_patients

who are treated with ACTHor

e

_.t

g so oo

cortisone,

and in the

_patients

with an

endogenous

$ U)e o abundance of adrenal cortical hormones due to

Cushing's syndrome.

The cerebral blood vessels

areknown to show

_profound

vasomotor_responses

to changes in blood CO2 tension, 02 tension, and 1

u"'

pH (12), but the

observed

hemodynamic

altera-.8,

l|*B|>

|tions

could notbecorrelated with changes in blood

>

s-8 N _ gases. It is unlikely that the increases in arterial

a_{to and venous}

_CO2

_{content during treatment, which}

C'.. ^ 0are

suggestive

of the presence of mild metabolic

WOtw8ow

_alkalosis,

_{are related to the cerebral circulatory}

changes

that

_occurred,

since

_experimental

alkalo-sis in humansis known to dilate rather than con-strict cerebral vessels and is accompanied by an

o

.s

, Eg increase in CBF

(13).

It seems most

likely

that the hemodynamic

changes

in the cerebral

EFFECT OF ACTH AND CORTISONE ON CEREBRAL BLOOD FLOW 3

exerts a specific local effect on the cerebral vascu-lature. In an occasional individual there occurs a reduction in CBF, of such magnitude and re-versibility when the drug is withdrawn, to sug-gest strongly that a degree of cerebral

vasocon-striction hasbeen induced that is out of proportion

to-the increase in total peripheral resistance mani-fest in that individual. The cause for this ap-parent local increase in CVR in an occasional pa-tient is not known. Changes in blood 02 content or CO2 content of sufficient magnitude -to ac-count for them did not occur; they are too large tobewithin the range of normal variation; we have noreason to believe they are the result of technical errors;they do not appear to be related to changes in the clinical course of the diseases for which the

patients were being treated.

In spite of the profound metabolic effects of

ACTH

andcortisone,and the fact that the adrenal

steroidstraversetheblood-brain barrierand might

easilyaffectcerebral enzyme systems, the adminis-tration of these hormones did not alter the total

oxygen or glucoseconsumptionof thebrain. How-ever, all thepatients exhibited some change in

per-sonality of greater or lesser degree during the course of treatment. Most of them developed a

positive sense of well being, irrespective of the clinical status of their disease; some became eu-phoric, one (W. F. G.) suddenly became

belliger-ent and expressed ideas of persecution. One of

the patients (L. R. C.) who received ACTH for several months became frankly psychotic after a long period of progressive change in mood.

Nocorrelation exists betweenthese mental

changes

and the cerebral circulatory and metabolic

func-tions that were measured. These data support the concept that the bulk of oxygen and

glucose

consumed by the brain is used to maintain its

structural integrity and throw no

light

on the

biochemicalor

biophysical

changes associated with

changes in mentation.

SUMMARY

1. Measurements of cerebral

circulatory

and metabolic functions were made in a series of pa-tients before, during, and after treatment with cortisone and ACTH. Similar studies were made in two patients with

Cushing's syndrome.

2. Parallel increases in the means of arterial

blood pressure and cerebral vascular resistance

occurred in both the cortisone and ACTH treated

patients. The mean cerebral blood flow remained unchanged. The results are interpreted to mean that the cerebral circulation shares equally in an increase in general peripheral vascular resistance. ACTH and cortisone do not appear to exert a specific, local effect upon cerebral blood vessels.

Similar

changes in thecerebral

circulation,

that is,

parallel increases in MABP and in CVR, with normal CBF were found in two subjects with Cushing's syndrome.

3. Significant changes in the mean cerebral

utilization of oxygen and glucose did not occur during the administration of cortisone or ACTH.

Cerebral oxygen and glucose utilization were nor-mal in patients with Cushing's syndrome.

4. These studies provide no explanation for the mental changes thatoccurred during the

adminis-tration of cortisone and ACTH.

ACKNOWLEDGMENTS

This work was done with the technical assistance of Mrs. Angeline M. Hayes and Miss Mary Sue McCall. Mr. Tyree Loving alsogavevaluable assistance.

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