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OBSERVATIONS ON ADRENAL CARCINOMA WITH SPECIAL REFERENCE TO THE EFFECTS OF AMPHENONE

ROY HERTZ, M.D., PH.D., D. M. BERGENSTAL, M.D., PH.D., HERBERT A. LUBS, M.D., AND SILAS J. JACKSON, M.S.

T HE functional nature of most tumors of the adrenal cortex is clinically manifested by the syndrome of hyperadrenocorticism. This syndrome is characterized by varying de- grees of hypertension, diabetes, obesity with rounding of the face, polycythemia, mental aberrations, osteoporosis, acne, and masculini- zation, or less commonly, feminization. The several patterns in which these features arise have been extensively described by others.12, 13

This report is primarily concerned with the suppression of certain of the biochemical and clinical features of this syndrome by 1,2-bis- (p-aminophenyl)-2-methylpropanone-1 dihydro- chloride (amphenone B) in seven patients with adrenal carcinoma. In addition, certain en- docrinological features presented by these seven patients and one additional case will be described, particularly with respect to their responsiveness to stimulation by adrenocorti- cotropic hormone (ACTH) and to suppression by corticoid administration. Similar studies have been made by other investigators in eight additional cases. Their observations are es- sentially the same as ours and are reported elsewhere.3, 16

Our earlier studies concerning the endocrine effects of amphenone in animals and man have been previously reported.1, 5-7, 17 These obser- vations indicated that amphenone depresses both adrenal and thyroid function in much the same manner as antithyroid drugs block the hormonal output of the thyroid alone. These inhibitory effects are mediated through peripheral interference with the biosynthesis of thyroid and adrenal hormones. This sup- pression is accompanied by a nonproductive

FIG. 1. Case 1. N.G., a 35-year-old white woman with adrenocortical carcinoma.

40

BLOOD CORTICOIDS

ACTH

30

(y/100cc)

20

AMPHENONE (p.0)

10

0

17,21-OH CORTICOIDS

30

20

mgm

24 H. URINE

10

0

100

BO

17 KETO-

STEROIDS

60

mgm

40

24 H. URINE

20

0

AMPHENONE

10

ACTH

(Gm/DAY)

5

40F

P.O.

0

1

11

21

3

41

51

DAY OF STUDY

hypertrophy of the thyroid and adrenals that results from the uninhibited tropic action of the anterior pituitary upon these end organs.5, 7 It therefore seemed desirable to determine the effect of amphenone in patients with hyper- adrenocorticism due to adrenal carcinoma.

MATERIALS AND METHODS

The essential clinical features of the eight cases included in this study are presented in brief abstract and in Tables 1 and 2. They all represent advanced cases with recurrent or metastatic disease. Seven of the patients had had one or more surgical procedures followed at varying intervals by clinically apparent or chemically detectable evidence of recurrence. The remaining patient initially exhibited mas- sive hepatic metastases and signs of vena caval obstruction that militated against any attempt: at surgical resection of the primary tumor. Diagnosis was confirmed in all cases by his-

From the Endocrinology Branch, National Cancer Institute, of the National Institutes of Health, Public Health Service.

Presented at the Annual Scientific Session of the American Cancer Society, Inc., New York, New York, October 30, 1956.

Part of the 1,2-bis(p-aminophenyl)-2-methylpropa- none-1 dihydrochloride (Amphenone B) used in these studies was provided by the Upjohn Company, Kala- mazoo, Michigan.

Received for publication February 25, 1957.

TABLE 1 ADRENOCORTICAL CARCINOMA: CLINICAL BEHAVIOR
PatientN.G.V.G.G.W.V.F.G.T.L.B.P.V.R.S.
Case no.12345678
Age at onset of symp., yr.3128164131133026
SexFFFFMMFM
Masculinization
Hirsutism+*+++- f-+++-
Clitoral hypertr.+--++
Acne++++++++
Cushingoid features
Obesity++++++++-++
Av. b. p.130/90140/95120/90150/100140/100110/80140/90120/80
High b. p.150/110170/110200/140225/120200/140140/90200/120140/90
Amenorrhea+-+++.. .
Purple striae------+-
Abn. glucose tol.+-++++...+. . .
Moon facies+++++++±
Plethora+++-+++-
Edema++++-+++-++
Bizarre behavior+++土++-++
Low potas.-++-----
Survival time
From diag.3 yr.1 mo.1} yr.> 2 yr.9 mo.6 mo.> 2 mo.> 4} yr.
From prob. onset3} yr.3 mo.2 yr.> 4 yr.1} yr.1 yr.> 10 mo.> 4} yr.
StatusDiedDied withDied withLiving,Died withied afterLiving, noLiving,
elsewhererenal failure & jaundicev. caval obst. & renal failuresteroids elevatedv. caval obst.hypophys. with v. caval obst. & renal failureapparent dis.extens. abd. & pulm. dis.
Metastases
Local extension?+++++-+
Liver?++-++-+
Lungs++--++-+
Renal v. or inf. v. caval obst.?-+-++-?
Other sitesNo dataNoneNoneV. caval invasion resectedDia- phragm, peri-Dia- phragm, omentum-- Phys. exam., X-ray, laparot. four times
Basis for statementsX-ray, no autopsyAutopsyAutopsyPhys. exam., X-ray, laparot.toneum, colon, omentum AutopsyAutopsyPhys. exam., X-ray, laparot. twice

*+- Present at some time in the patient’s course.

1 — Absent at all times.

#++ Marked at some time in the patient’s course.

topathological study of tissue obtained at sur- gery or autopsy.

These observations were carried out on pa- tients in a research ward who were under the constant supervision of especially trained medi- cal and nursing personnel. The toxic manifes- tations5 of amphenone-somnolence, anorexia, gastric irritation, methemoglobinemia, and drug rash-were carefully watched for. Clini- cal observations included caloric intake, fluid output and intake, body weight, insulin re- quirement, glucose-tolerance curves, electrolyte status as determined by frequent determina- tions of plasma and urinary sodium and po- tassium, hematological status, alterations in

size and consistency of palpable, visible, or radiologically demonstrable tumor masses, al- terations in intensity of mental symptoms, fa- cial plethora, hypertension, acne, striae, or hirsutism, alterations in plasma level and uri- nary levels of 17-hydroxycorticoids as deter- mined by the method of Silber and Porter 15 as modified by Peterson et al.,11 and in uri- nary 17-ketosteroids as determined by the method of Callow et al.2

ACTH stimulation tests were carried out by the intravenous infusion of 25 to 40 units of ACTH in 500 cc. of saline or 5 per cent dextrose, usually during an eight-hour period, with ap- propriately timed determinations of plasma

FIG. 2. Case 2. V.G., a 28-year-old woman with adrenocortical carcinoma.

AmphenoneIV

200

Amphenone

p.Q.

BLOOD 17,21-OH CORTICOIDS (y/100cc)

150

terminal

100

158 88

50

(BLOOD PRESSURE)

160

90

154

100

BO

130

84

0

HO

BO

84

50

5¢

100

17,21-OH CORTICOIDS mgm 24 H. URINE)

75

50

25

0

(338)

250

200

17 KETO- STEROIDS mgm 24 H. URINE)

150

100

50

0

8

P.O.

AMPHENONE (Gm/DAY)

4

IV

0

1

6

Il

16

21

26

31

36

DAY OF STUDY

17-hydroxycorticoids and urinary 17-hydroxy- corticoids and 17-ketosteroids as already de- scribed. Suppression tests were carried out by similar studies before and after oral admin- istration of 0.5 to 1.0 mg. of 41-9a-fluoro-hy- drocortisone (A1-Fluoro F) each at six-hour in- tervals for three to four days as described by Liddle et al.9

Amphenone was administered orally in 0.25- gm. and 0.5-gm. capsules, according to the dosage regimen indicated for each patient. In patients complaining of gastric irritation, the medication was given with milk or antacids. Dosage and intervals between doses were ad- justed in each case to avoid undue somnolence or lethargy. Medication was discontinued in the event of severe gastrointestinal reaction, met- hemoglobinemia, or drug eruption. When am- phenone was administered intravenously it was given in 1 per cent solution in saline or in 5 per cent dextrose in water at the rate of about 1 gm. per hour. Local tolerance was good in all cases except for a slight burning sensation noticed by most patients just as the infusion was begun. During such infusions the pulse, blood pressure, respiration, and respon- siveness of the patient were checked at ten-

minute intervals and the patient was con- stantly attended. Infusion was slowed or arrested in accordance with the patient’s reac- tions. Usually only minor adjustments in rate of flow were indicated.

Five of the patients reported here have died and an autopsy was performed on four. Three patients survive and continue under observa- tion at the present time.

RESULTS AND DISCUSSION

The observations are summarized in Tables 1, 2, and 3, in the case abstracts and in Figs. 1 to 7. The data warrant the conclusion that amphenone proved capable of markedly re- ducing the steroid-hormone output in six of the seven patients receiving this drug. This re- duction in hormone output was acutely de- monstrable after a single intravenous infusion, or it could be maintained for more prolonged periods by continued oral medication. This suppression was variously manifested by a re- duced plasma 17-hydroxycorticoid level, re-

FIG. 3. Case 3. G.W., an 18-year-old Negro woman with adrenocortical carcinoma. Single asterisk indicates no recurrence; double asterisk, recurrence.

AMPHENONE

BLOOD

100

ACTH

AFF

ACTH

17,21-OH

75

CORTICOIDS (y/100cc)

50

25

10

0

50

17,21-OH CORTICOIDS mgm

25

(24H. URINE

10

0

OLIGURIA

200

17 KETO- STEROIDS

150

mgm

100

24 H. URINE

50

20

OLIGURIA

0

8

3

AMPHENONE Gm /DAY

*

IV

4

0

OTHER

ACTH

AIFF

Rx/DAY

25u

ACTH 40M

4

ngm

I

6

11

I

6

11

16

21

JUNE 1956

DECEMBER 1956

DAY OF STUDY

TABLE 2 ADRENOCORTICAL CARCINOMA: FUNCTIONAL TESTS
Urinary steroids, mg./24 hr.t
Case no. Patient Status of tumorDrugDosageResult*17-Ketosteroids17,21-Hydroxy- corticoidsBlood 17,21-hydroxy- corticoids, µg./100 cc.#Comment
ReactionValue or rangeReactionValue or rangeReactionChange in value or range
1Prether.. . .. ..47-9511-2324-32
N.G.ACTII40 u .; I.V .; 3 hr.-.........-32-+30 (3 hr.)...
ActiveAmph.2-12 gm .; P.O .;土30-72+0-14-25-43No rebound
24 hr .; 32 days
2Prether.. ... ..132-196. . .51-113...85-104Marked rebound after amph .; blood
V.G.corticoid to 190 µg./100 cc .; urin.
Amph.4-8 gm .; P.O .;++88-181+13-48+36-82corticoid to123 mg./24 hr .; 17-ketos.
Active24 hr .; 11 daysto 338 mg./24hr.
Amph.8 gm .; I.V .; 8 hr.+-132§+29+198->36 (8 hr.)CANCER I.V. tests 2 days apart, with down- during
Amph.6 gm .; I.V .; 8 hr.++18+2+32->21 (8 hr.)July-August ward progression of all values the 3-day period; oliguria
3
G.W.Prether....558-14
InactiveACTH40 u .; I.V .; 8 hr.-5-6-14-+33 (8 hr.)...
postop.Prether.......33-221. . .15-2634-40...
Active41-Fluoro F4 mg .; P.O .;
24 hr .; 4 days--25-55-25-38-52-581957 ...
ACTH40 u .; I.V .; 8 hr.++200+51+43->111 (8 hr.)...
Amph.7 gm .; I.V .; 8 hr.++8+1.7+ .47->6 (7 hr.)No rebound
4Prether.. ..53-70...40-45.........
V.F.
Active bef.Amph.8 gm .; I.V .; 10 hr.+-56+38 (day of op.)+38-12No rebound
2d op.14 (day
postop.)
InactivePrether....2-62-7...4-14
postop.ACTH25 u .; I.V .; 8 hr.士-3±11士12->24 (8 hr.)...
ActivePrether..... ..19-34. ..15-25. ..15-26...
41-Fluoro F4 mg .; P.O .;...-80-89-52-60-25-29
24 hr .; 4 days
ACTH40 u .; I.V .; 8 hr.-30-27+26->37 (8 hr.)
Amph.8 gm .; I.V .; 8 hr.H+-45+11+22-+0 (15 hr.)No rebound
5Prether.. ... . .6-1317-2436-37...Vol.
G.T.ACTH25 u .; I.V .; 4+....... .....+32-+93 (4 hr.)10
TABLE 2-Concluded ADRENOCORTICAL CARCINOMA: FUNCTIONAL TESTS
Urinary steroids, mg./24 hr. ;
Case no. Patient Status of tumorDrugDosageResult*17-Ketosteroids17,21-Hydroxy- corticoidsBlood 17,21-hydroxy- corticoids, ug./100 cc.#Comment
ReactionValue or rangeReactionValue or rangeReactionChange in value or range
5 (Cont'd.)
G.T.
Activehr .; twice37-+91 (4 hr.)
Amph.9.5 gm .; I.V .; 8 hr.+-13-25+28->13Marked rebound necessitated 2d I.V. course
6.5 gm .; I.V .; 7 hr.?-17-22?322->64. ..
6Prether....25...17...28-57...
L.B.ACTH40 u .; I.V .; 8 hr.+-15-11+51->110 (8 hr.)Oliguria
Active
7Prether.. ..29-3725-38...23-24
P.V.41-Fluoro F2 mg .; P.O .;--26-37-28-33-22-274-gm. dose stopped because of tachy-
Active24 hr .; 6 dayscardia & low serum potassium
preop.4 mg .; P.O .;
24 hr .; 1 day
ACTH40 u .; I.V .; 8 hr.--3637-25-+30 (8 hr.)No rebound
Nilevar100 mg .; I.M .;--26-34-22-34
24 hr .; 5 days
Amph.6 gm .; I.V .; 8 hr.--26-25-29->24No rebound
InactivePrether.. .... .2-5. . .4-10...
postop.Amph.6 gm .; I.V .; 8 hr. 5-8 gm .; P.O .; 24 hr .; 3 days- 土- -3 6-11- -6 2-1013->12No rebound
3-15
8Prether.......54-64...35-43...20-30
R.S.41-Fluoro F4 mg .; P.O .;--75-128-46-58-23-47
Active2 hr .; 4 days
ACTH40 u .; I.V .; 8 hr.+-55-45+30-+81 (8 hr.)
Amph.10 gm .; I.V .; 8 hr.++256+30->7 (8 hr.)Rebound in 17-ketos. to 128 mg./24 hr.

*Positive reaction (+) indicates a significant change from the range of values prior to treatment in any one of the three modalities measured.

+Normal range for urinary 17,21-hydroxycorticoids is 2 to 10 mg. per 24 hr .; for urinary 17-ketosteroids, 5 to 15 mg. per 24 hr. for women and 10 to 20 mg. per 24 hr. for men.

Normal range for blood 17,21-hydroxycorticoids is 5 to 25 ug. per 100 cc.

§Where a single value is given it represents the 24-hr. period in which the test was made.

EFFECTS OF AMPHENONE ON ADRENAL CARCINOMA . Hertz et al.

TABLE 3 SUMMARY OF FUNCTIONAL TESTS
TestNo. pt.No. pos.No. equiv.No. neg.
A1-Fluoro F suppression4004
ACTH stimulation7412
Amphenone suppression7601

duced urinary excretion of 17-hydroxycorti- coid, and to a lesser degree, a reduced urinary excretion of 17-ketosteroid (cases 1 to 5 and case 8). Also, in cases 2, 5, 7, and 8 a reduction of pre-existing hypertension was seen. The only patient in our series requiring insulin (case 5) was maintained without insulin dur- ing amphenone therapy. Similar effects of am- phenone upon insulin requirement have been previously reported.6, 16

In each instance the manifestations of reduced corticoid function proved rather promptly reversible. After a single intravenous infusion of amphenone, the plasma-corticoid values returned to pretreatment levels in from twelve to forty-eight hours (cases 2, 3, 4, 5, and 8). After prolonged oral administration of am- phenone, the plasma and urinary 17-hydroxy- corticoid values returned to pretreatment levels in from twenty-four to forty-eight hours after

FIG. 4. Case 4. V.F., a 45-year-old Negro woman with adrenal carcinoma. Single asterisk indicates no recur- rence; double asterisk, recurrence.

BLOOD

AMPH

17,21-OH

40

ACTH

ACTH

CORTICOIDS (y/100cc)

AMPH

AFF

30

20

D

10

00

00

0

60

17,21-OH CORTICOIDS

40

mgm 24H. URINE

20

0

(312)

17 KETO- STEROIDS

80

60

mgm 24H. URINE

40

20

0

AMPHENONE (Gm/DAY)

8

TUMOR -EXCISION

2ND EXCISION

4

**

*

**

OTHER Rx /DAY

ACTH

ACTH

Δ. FF

40 K JV

40μιν

4 mgm

1

30 1 3 6

I

357

I

6

11

16

21

26

31

1

1955

1956

DAYS

1957

FIG. 5. Case 5. G.T., a 33-year-old white man with adrenocortical carcinoma.

o(3Hly)

(180

BLOOD 17,21-OH CORTICOIDS (y/100cc)

140

(BLOOD

PRESSURE)

100

75

(130)

90

(170)

120

( 170)

120

(158)

50

0

25

0

40.

76

50

40

17,21-OH CORTICOIDS

30

mgm

20

24H.URINE

10

0

17 KETO- STEROIDS

30

20

mgm

24 H.URINE

10

0

P.O

10

IV

AMPHENONE

5

(Gm/24 H.)

0

1

6

11

16

21

26

31

36

JULY

1956

AUGUST

DAY OF STUDY

discontinuation of the drug (cases 1 and 2). In two instances the cessation of amphenone administration was followed by a marked but transient exacerbation in the biochemical and clinical manifestations of hyperadrenocorti- cism (cases 2 and 5). The most notable clinical features of this rebound period were marked hypertension and exacerbation in the mental aberrations previously exhibited by the pa- tient. This was associated with excessively high plasma and urinary 17-hydroxycorticoid levels. In case 5, resumption of intravenous amphe- none therapy again suppressed these distress- ing features of extreme hyperadrenocorticism.

In none of the cases here reported was there sufficient abnormality in electrolyte metabo- lism to permit an unequivocal demonstration of an effect of amphenone administration. In addition, clinical exigencies arising from the extreme illness of these patients precluded sufficiently controlled electrolyte intake to war- rant firm conclusions as to possible effects of amphenone on electrolyte balance. Only two of these patients exhibited distinct hypokalie- mia (cases 2 and 3) and this responded promptly to potassium administration. Nevertheless,

FIG. 6. Case 7. P.V., a 30-year-old woman with ad- renocortical carcinoma.

40

AFF

ACTH PAMPH

BLOOD

17,21-OH

30

CORTICOIDS

20

(y/100cc)

10

0

40

17,21-OH CORTICOIDS

30

mgm

20

24 H. URINE

10

0

40

30

17-KETO-

STEROIDS

20

mgm

24 H. URINE

10

0

AMPHENONE

8

IV

TUMOR EX.

Gm/DAY

4

00mgm

0

DAY

NILEVAR

CORTISONE

OTHER

A FF

ACTH

1

40LIV

200

Rx

2

4

-75

I

6

11

16

21

26

31

36

41

DAY OF STUDY

Liddle et al.10 and Renold et al.14 have pre- sented evidence indicating the suppression of aldosterone excretion by amphenone in man.

Amphenone presents sufficient toxic effects to limit seriously its prolonged administration except under such extreme clinical circum- stances as those presented by the type of cases reported here. The somnolence experienced by practically all patients receiving effective amounts of amphenone limits the dose that can be administered for any prolonged period. The additional toxic manifestations of drug eruption, methemoglobinemia, and gastric dis- tress have been fully described elsewhere.5

Notwithstanding these practical limitations, our experience warrants the conclusion that amphenone may be used safely for brief pc- riods of time in order to produce a prompt but reversible suppression of the untoward metabolic and psychiatric manifestations of hyperadrenocorticism. Thus, amphenone pro- vides an initial model for the derivation of less toxic pharmacological agents for adrenal cor- tical suppression.

In no instance was there clinical or his- tological evidence that amphenone-induced

suppression of the hormonal function of these adrenal tumors was accompanied by any al- teration in their characteristic growth and ex- tension. The most frequently recurring lethal pattern was that of progressive obstruction of the vena cava, with ultimate occlusion of the renal veins, anuria, and death in uremia. In the only instance (case 2) in which sufficient amphenone was given to permit any infer- ence as to the direct action of the drug upon the tumor tissue, no distinctive histological effect was noted. In this instance the drug was given just prior to death.

The tabulated data show that four of the seven patients tested responded in an extreme manner to ACTH stimulation. This was mani- fested by a prompt rise in plasma-corticoid val- ues to levels exceeding those observed in eucor- ticoid patients similarly treated with ACTH. Thus the usual eucorticoid response to ACTH in our laboratory produces an elevation in the plasma-corticoid values from an initial level of 15 to 25 µg. per 100 cc. to a range of 40 to 60 µg. per 100 cc. In the ACTH-responsive carcinoma patients these values were 111, 93,

FIG. 7. Case 8. R.S., a 30-year-old white man with adrenocortical carcinoma.

BLOOD

100

AFF

17,21-OH

75

CORTICOIDS

(Y/100cc)

50

25

0

50

17,21-OH

CORTICOIDS

25

mgm

(24 H URINE

0

100

75

17 KETO-

STEROIDS

50

mgm

24 H. URINE

25

0

AIFF

RX

ACTH

AMPHENONE

40μ

8 Gm IV

4 mgm

1

6

11

16

DAY OF STUDY

81, and 110 µg. per 100 cc. Conversely, all four patients who had undergone corticoid- suppression tests failed to show any evidence of reduction in corticoid output after admin- istration of doses of A1-Fluoro F that would have been adequate to produce profound sup- pression in the eucorticoid subject. Accord- ingly, it would appear inadvisable to general- ize as to the precise diagnostic significance of such functional tests in differentiating hyper- plastic from neoplastic lesions of the adrenal gland.8

The varying clinical manifestations of hy- peradrenocorticism in patients with adrenal carcinoma may be appreciated from perusal of Table 1. Our series included practically all of the classical features already referred to ex- cept that of feminization.

A noteworthy clinical aspect is the obvious mental derangement exhibited by five of our patients. Careful neurological and electro- encephalographic study revealed no structural basis for these effects. The pattern included euphoria, depression, depersonalization, dis- orientation, combativeness, hallucinations, and paranoia. Since similar manifestations are seen in patients treated with exogenous corticoids, it may be considered that such phenomena in patients with adrenal carcinoma are also at- tributable to excess endogenous corticoids. The mechanism of the favorable effect of am- phenone on these mental symptoms is ob- scured by the fact that the compound is known to have a direct depressant action on the cen- tral nervous system.4 Thus its effect in this regard may not be directly or entirely related to its effect upon endogenous corticoid pro- duction.

It should be emphasized that the observa- tions reported here are regarded to be of more pharmacological than therapeutic interest. It is hoped that these studies may stimulate fur- ther effort toward the development of a more widely acceptable chemical agent for adrenal cortical suppression.

SUMMARY

1,2-Bis(p-aminophenyl)-2-methylpropanone-1 dihydrochloride (amphenone B) was observed to reversibly suppress the clinical or biochemi- cal features of hyperadrenocorticism in six of seven adrenal-carcinoma patients. Adrenal- stimulation tests with adrenocorticotropic hor- mone (ACTH) indicated that four of seven pa- tients responded to such stimulation. Suppres-

sion tests employing 41-9a-fluoro-hydrocorti- sone (41-Fluoro F) in four cases failed to pro- duce any significant reduction in either plasma- or urinary-corticoid content in any case.

CASE REPORTS

Case 1. N.G. was a 35-year-old white woman. In April, 1951, a left oophorectomy had revealed a dermoid cyst. A few months later the patient became pregnant and dur- ing this pregnancy noticed an excessive growth of body hair, which persisted thereafter. In the next year the patient alternated between amenorrhea and bouts of vaginal hemorrhage. She developed a moon face early in 1953. In May, 1953, the patient underwent an explora- tory operation. A left-adrenal tumor was re- moved, with a resulting microscopic diagnosis of adrenocortical carcinoma. Postoperatively there was a marked regression of the moon face, loss of body hair, and return of a normal menstrual pattern. She received ACTH intra- muscularly for three months postoperatively. Early in 1955, after a period of good health, the patient noticed regrowth of facial hair, ankle edema, scanty menses, nervousness, acne, and a 12-1b. weight gain. In May, 1955, she received roentgen-ray therapy to her chest and flank, without beneficial effect. Symptoms con- tinued to progress and she was admitted to the Clinical Center, National Institutes of Health, Bethesda, Maryland, in June, 1955.

Physical examination revealed a blood pres- sure of 140 over 70 mm. of mercury, a moon facies, excessive facial hair, plethora, centri- petal obesity, and a slightly enlarged clitoris, but no striae. There were multiple bizarre mental symptoms. There was marked eleva- tion of the 17-ketosteroids, moderate elevation of the urinary 17,21-dihydroxycorticoids, and slight elevation of the blood 17,21-dihydroxy- corticoids. The glucose-tolerance curve was di- abetic in type, but the fasting blood sugar remained normal. There was no rise in blood corticoids resulting from a three-hour ACTH test. She received a thirty-two-day course of amphenone, varying in dose from 2 to 12 gm., orally, with a drop to undetectable levels of urinary 17,21-dihydroxycorticoids but no change in blood corticoids or urinary 17-keto- steroids. Roentgenograms revealed multiple metastatic pulmonary nodules and these were unchanged by the course of amphenone. The patient was discharged with her condition un- changed and died in another hospital early in 1956. No autopsy was carried out.

Case 2. V.G. was a 28-year-old woman. In early December, 1955, the patient noticed rather marked weight gain, particularly about

her waist and face. However, an employment physical examination in mid-December includ- ing blood-pressure test and chest roentgeno- gram, gave normal findings. Late in Decem- ber she noticed rather marked acne that was followed in a few days by ankle edema, bouts of confusion, paresthesias, blurred vision, emo- tional lability, and severe generalized weakness. Her blood pressure was said to be more than 200 mm. of mercury, systolic. In January, 1956, she was admitted to Highland Hospital, Roch- ester, New York, where a left upper-quadrant mass and physical findings compatible with Cushing’s syndrome were noted. Urinary 17- ketosteroids and 17-hydroxycorticoids were elevated and the glucose-tolerance curve was abnormal. A low potassium was also found (1.9 mEq. per liter). Multiple fine pulmonary nodules were seen by roentgenogram. The patient was referred to the Clinical Center February 2, 1956; her blood pressure was 170 over 110 and she was obese, hirsute, and ple- thoric, with ankle edema and moderate acne over her chest. There was a left upper-quad- rant mass, a slightly enlarged liver, and nor- mal genitals. The patient was having a normal menstrual period on admission. The earlier laboratory findings were confirmed and re- view of the employment chest roentgenogram showed (in retrospect) that there were fine

nodules throughout the chest at the time it had been taken. The patient received an eleven-day course of amphenone (average dose 6 gm. per day, orally), with a significant drop in the markedly elevated blood corticoids, and in the urinary 17-ketosteroids. The left upper- quadrant mass, however, continued to enlarge.

After cessation of oral administration of amphenone there was a marked rebound in all of her steroids, with the blood corticoids as high as 198 ug. per 100 cc. In conjunction with this the patient had an acute psychotic bout that was controlled with intravenous am- phenone therapy. In the last week of the pa- tient’s life she received three intravenous courses of amphenone, with a drop to normal or near-normal levels in both blood and urinary corticoids and a marked reduction in blood pressure.

The patient’s downward course continued and was marked by increasing edema, a rise in blood-urea nitrogen, and oliguria. Her ter- minal course was also marked by intermittent peripheral vascular collapse and coma.

Although the patient had had a 4-plus sugar reaction with a trace of acetone on admission, she had required no insulin or specific man- agement of her diabetes. The initially low blood potassium of 2.4 mEq. per liter re- sponded well to added potassium and thus did not present a clinical problem. There was,

however, a terminal rise in serum bilirubin.

At autopsy the presumptive diagnosis of adrenocortical carcinoma was confirmed micro- scopically, and there was extensive disease in the liver and lungs, with local extension of the primary tumor, which was 15 cm. in diameter. There was, however, no invasion of the vena cava or of the renal veins. Microscopically, the kidneys showed evidence of a lower-nephron syndrome. The histological features of the tumor tissue were not remarkable as to cellu- lar fat content or extent of necrosis.

Case 3. G.W. was an 18-year-old Negro woman. In November, 1954, the patient had noticed sudden and marked weight gain, par- ticularly about her abdomen, breasts, and face. Amenorrhea, headaches, nausea, and vomiting accompanied the weight gain. In January, 1955, her blood pressure was 130 over 74 and she was obese and had excessive facial hair. In February a blood pressure reading as high as 200 over 140 was obtained and the patient became quite listless and depressed. On May 2, 1955, an “orange-size,” right-adrenal tumor was removed at the University of Virginia Hos- pital, Charlottesville, Virginia, with a micro- scopic diagnosis of adrenocortical carcinoma. There was microscopic invasion of the capsule but no obvious extension elsewhere. Because of two bouts of adrenal insufficiency, it was several months after the operation before cor- tisone could be completely discontinued. There was, moveover, a marked change in her ap- pearance, with loss of obesity, hirsutism, and subjective complaints. Normal menses re- turned and her blood pressure dropped to normal levels. The patient was admitted to the Clinical Center for evaluation in June, 1956, thirteen months after the tumor was re- sected. There was no clinical evidence of dis- ease and steroid determinations were within normal limits. It is interesting to note. how- ever, that she did not respond to ACTH stimula- tion. In August, 1956, the patient noted a dull epigastric pain that was followed by reappear- ance of facial hair and by weight loss. She again became listless and in October, 1956, developed progressive edema of both legs. Her blood pressure remained low. She was read- mitted to the Clinical Center in December, 1956, when she appeared acutely ill, with mas- sive edema of both legs extending to the level of the upper sacrum. Her blood pressure was 120 over 90 and there was moderate ascites and a hard, tender, upper abdominal mass that ap- peared to be both liver and tumor. Although there was some facial hair, she was definitely not cushingoid in appearance and was not obese. Although the patient had had an ele- vated fasting blood sugar in March, 1955. be- fore the tumor was resected, and a potassium

as low as 2.9 mEq. per liter, at no time after the resection of the tumor did such abnormal- ities recur. When seen in June, 1956, the glucose-tolerance curve was normal. However, on this admission a definitely diabetic curve was noted, although the fasting blood-sugar level remained normal. At no time did she have clinical diabetes or require insulin. The patient’s urinary steroids were markedly ele- vated and the blood-corticoid level was high. It rose from 43 to 111 ug. per 100 cc. with ACTII stimulation but there was no suppres- sion of any steroid values during a four-day suppression test with 41-Fluoro F. There was, however, a marked drop in both blood and urinary steroids after an eight-hour amphe- none infusion. The patient’s course was rap- idly and progressively downhill and she died twenty-four days after admission and after a week of severe oliguria and progressive uremia. At autopsy there was moderate local extension of tumor, with invasion and complete obstruc- tion of the inferior vena cava and diffuse liver metastases, but no extra abdominal disease.

Case 4. V.F. was a 45-year-old Negro woman. In 1952 the patient had noticed slight acne; two years later she developed facial hair. She had a history of a goiter and hypertension for more than twenty years but had been well and had given birth to eight normal children in this interval. In 1955, because of further in- crease in blood pressure and in the size of the goiter, and because of abnormal behavior and hoarseness, the patient was admitted to Phila- delphia General Hospital, Philadelphia, Penn- sylvania, for diagnosis. The findings included slight temporal baldness, acne, facial hair, obesity, amenorrhea, clitoral hypertrophy, dia- betic glucose-tolerance curve, elevated 17-keto- steroids, and roentgen-ray evidence of a right- suprarenal mass. A large right-adrenal mass was removed surgically, with a resulting diag- nosis of adrenal carcinoma (March, 1955). The symptoms regressed after this but returned early in 1956, and the patient was readmitted in June, 1956. Her blood pressure was 255 over 120 and the clinical picture resembled that seen on her earlier admission. At lapa- rotomy recurrence of the tumor, with invasion of the vena cava and diaphragm, was seen. The tumor mass was partially resected and radon seeds implanted. Postoperatively the blood pressure dropped to 140 over 80 but the patient remained amenorrheic and had per- sistence of the facial hair. She was first seen at the Clinical Center in September, 1956, and no biochemical, clinical, or radiological evi- dence of tumor was found. She was readmitted in January, 1957, with an interval history of weight gain, facial rounding, and further tem- poral balding, but no disease that was clini-

cally apparent on physical examination. Both urinary 17-ketosteroids and 17-hydroxycorti- coids were elevated and the patient showed an equivocal response to ACTH, no suppression on A1-Fluoro F, but a marked suppression with intravenous amphenone. Her condition re- mains good and at this time further therapy is being considered.

Case 5. G.T. was a 33-year-old white man. Because of exposure to carbon disulphide at work, the patient’s blood pressure had been followed closely. In June, 1955, his blood pres- sure was elevated and it continued to increase progressively until by January, 1956, in spite of therapy, it had risen to 220 over 120. At this time he developed right upper-quadrant pain; an exploratory operation revealed bloody ascitic fluid and a diagnosis of pancreatitus was made. Postoperatively, an intravenous pyelogram revealed a mass above the right kid- ney and the patient was operated on again in February. At this time a large tumor, invading the right kidney and diaphragm, was found. The microscopic diagnosis was adrenocortical carcinoma. Tests showed that he had diabetes, and he was treated with 15 to 30 units of in- sulin a day. The patient returned to work and was able to discontinue insulin. In June, 1956, however, he noticed weakness, puffiness of his face, obesity, and return of the diabetes, necessitating insulin administration. He was readmitted to the University of Virginia Hos- pital, Charlottesville, Virginia, in July, when pulmonary metastases and ankle edema were seen. On two occasions 25 units of ACTH intra- venously produced a rise in blood corticoids to more than 90 µg. per 100 cc. He was referred to the Clinical Center for evaluation. His blood pressure was 128 over 84. He was cush- ingoid in appearance; there was 4-plus ankle edema and a large right upper-quadrant mass. Both blood and urinary corticoids were elc- vated but the serum electrolytes were normal. Fasting blood sugar was 177 mg. per 100 cc. He received 9.5 gm. of amphenone intraven- ously over an eight-hour period, and the blood- corticoid level dropped from 28 to 13 ug. per 100 cc. On the third morning after this test, however, the patient became unmanageable and acutely psychotic; the blood-corticoid level had risen to 311 ug. per 100 cc. He therefore received a second infusion of amphenone in- travenously, with good control of his behavior and a sharp drop in his blood corticoids to 28 ug. per 100 cc. by the next morning, and he was then continued on amphenone by mouth. There was a moderate drop in both blood and urinary corticoids when amphenone was main- tained at a dose level of 6 or more gm. a day. When the dose of amphenone was lowered to 5 and then to 4 gm. per day, there was a

marked rise in both blood and urinary ster- oids (Fig. 2). This decrease in dose was neces- sitated by decreased tolerance of amphenone by the patient, as manifested by increasing lethargy, nystagmus, and vomiting. Thus it became inadvisable to attempt to continue to maintain adequate control of the functional symptoms and excessive steroid production with amphenone. He developed progressive uremia and oliguria and died fifty-eight days after admission. Initially there was some low- ering of the fasting blood sugar during am- phenone administration, but this rose when the dose of amphenone was increased. He did not, however, require any insulin during am- phenone administration. No regression of ab- dominal or pulmonary tumor masses was noted during amphenone therapy. At autopsy there was diffuse spread of the tumor throughout the peritoneal cavity, with invasion of the dia- phragm and vena cava and metastases in the liver and lungs.

Case 6. L.B. was a 13-year-old boy. In Oc- tober, 1955, the patient’s mother had noticed that the boy was gaining weight rapidly, par- ticularly about his abdomen and face, and shortly after this there was markedly increased facial acne, pubic and axillary hair, and easy fatigability. In May, 1956, a left upper-quad- rant mass was seen; his blood pressure was 130 over 90. An intravenous pyelogram revealed a left-suprarenal mass, and at laparotomy a large tumor was found invading the vena cava. The microscopic diagnosis was adrenocortical carcinoma. Removal of the tumor was incom- plete, but there was no evidence of disease elsewhere. Postoperatively there was good re- gression of the obesity and cushingoid appear- ance, and in June, 1956, normal 17-ketosteroid and 17-hydroxycorticosteroid values for twenty- four-hour urines were obtained. By Septem- ber, however, these had risen to abnormally high levels and he was readmitted to St. Louis Children’s Hospital, St. Louis, Missouri, in October because of dyspnea and left-flank pain and was referred to the Clinical Center for evaluation. His blood pressure was 110 over 75 but no cushingoid facies or obesity was noted, although there was marked edema from the level of L-4 downward. There was marked acne over his face and chest and a large right abdominal mass was noted. Genitals were un- remarkable. There was scanty axillary and pubic hair. His urine output averaged 500 cc. a day regardless of intake. Blood electrolytes were normal and the blood-urea nitrogen was 22 mg. per 100 cc. Both blood and urinary values were elevated and with ACTH stimulation there was a rise from 51 to 110 ug. per 100 cc. in the blood corticoids. Because of the excessive re- sponse to ACTH and a poor renal status, am-

phenone therapy was thought to be contrain- dicated and a hypophysectomy was carried out. The postoperative course was marked by poly- uria with fluid retention and a rise in blood- urea nitrogen to 55 and potassium to 7.1 mEq. per liter. He died four days after hypophysec- tomy. At autopsy a diffuse spread of tumor was seen throughout the abdominal cavity, with invasion of the inferior vena cava, renal veins, diaphragm, omentum, liver, and lungs.

Case 7. P.V. was a 30-year-old woman. In March, 1955, the patient was delivered of a normal male infant. The hypertension that had occurred during a previous pregnancy and this pregnancy persisted postpartum. She also noticed gradual but marked obesity in the year after this pregnancy, but her menses were normal. In March, 1956, she noticed palpita- tions, facial hair, acne, and flushing of her face. In the next few months there was a gen- eralized increase in body hair and a variety of emotional complaints. In June, 1956, a 17- ketosteroid determination showed a value of 25 mg. per twenty-four hours. Because bilater- ally enlarged ovaries were noticed on pelvic examination, she was operated on; no abnor- malities were found. The patient was referred to the Clinical Center with a diagnosis of Cushing’s syndrome. The initial findings in- cluded a blood pressure of 170 over 110, a marked moon face with centripetal obesity, acne, plethora, hirsutism, marked purple striae, a male escutcheon, and enlarged clitoris. A diabetic glucose-tolerance curve and elevated urinary steroids were noted but the blood cor- ticoids were normal. There was no change in adrenal function with the administration of A1-Fluoro F, ACTH, amphenone, or 17a-ethyl-17- hydroxy-19-nor-4-androsten-3-one (nilevar). A presumptive diagnosis of adrenocortical car- cinoma with Cushing’s syndrome was made. There was no evidence of metastasis. An ex- ploratory operation revealed an atrophic right adrenal and a necrotic tumor, 8x10x8 cm., replacing the left adrenal. There was no ob- vious invasion of surrounding tissues. Micro- scopic diagnosis was adrenocortical carcinoma. The patient’s postoperative course was char- acterized by several bouts of adrenal insuffi- ciency, and a maintenance dose of 100 to 200 mg. of cortisone seemed necessary on discharge. Her severely paranoid behavior was not al- tered, although the steroid excretion dropped to normal levels. Her postoperative course was complicated by the development of an acute condition within her abdomen, and on ex- ploration a 4-cm. loop of gangrenous small bowel was found and resected. Microscopic ex- amination revealed multiple venous throm- boses. No evidence of tumor was found. At the time of her discharge in December, 1956, there

was no evidence of disease by either examina- tion or functional tests.

Case 8. R.S. was a 30-year-old white man. In July, 1952, the patient had noticed a mass in his lower abdomen but otherwise was well. A laparotomy at the Veterans Administration Hospital, Clarksburg, West Virginia, revealed a large retroperitoneal tumor that was biop- sied; the microscopic diagnosis was adrenocor- tical carcinoma. In September, 1952, the pa- tient was operated on again and a mass weigh- ing 725 gm. was resected. At this time his blood pressure was 142 over 90 and his fasting blood sugar was normal. Since then the patient has had four additional operations, with removal of large amounts of tumor. From 1954 to the present time he has been maintained on 50 mg. of cortisone in an attempt to suppress the tumor function. In June, 1955, pulmonary metastases were seen by roentgenogram. Until the time of his admission to the Clinical Cen- ter in December, 1956, the patient continued to work. He felt well, denying all symptoms except slow but steady weight gain about his abdomen and face. There was no change in body hair. Six weeks prior to admission to the

Clinical Center, however, he noticed ankle edema and fatigability. On admission, his blood pressure was 140 over 94; he was slightly cushingoid in appearance, with some obesity and edema extending from the feet to the sacrum.

The patient’s abdomen appeared to be com- pletely filled with tumor from the costal mar- gin to the pubic symphysis except for a few soft areas in the flanks; there was limited ascites and marked generalized body hair. Both blood and urinary steroids were elevated and were not suppressed by 41-Fluoro F. There was a rise from 30 to 81 ug. per 100 cc. in blood cor- ticoids after ACTH stimulation. T’en gm. of amphenone given intravenously over an eight- hour period produced a drop in the blood- corticoid values from 30 to 7 ug. per 100 cc. and a corresponding drop in urinary corticoids and ketosteroids. There were no significant subjective changes during any of the tests ex- cept for slight drowsiness during amphenone administration. The blood pressure was not altered by the test. He is currently undergoing further evaluation at the Clinical Center. Elec- trolytes, blood-urea nitrogen, and fasting blood sugar continue to be normal.

REFERENCES

1. ALLEN, M. J., and CORWIN, A. H .: Chemical studics on pinacols obtained from p-aminoacetophenone and p-aminopropiophenone. J. Am. Chem. Soc. 72: 117-121, 1950.

2. CALLOW, N. H .; CALLOW, R. K., and EMMENS, C. W .: Colorimetric determination of substances con- taining grouping -Ch,-CO- in urine extracts as in- dication of androgen content. Biochem. J. 32: 1312- 1331, 1938.

3. GALLAGHER, T. F .; KAPPAS, A .; SPENCER, H., and LASZLO, D .: Influence of invasiveness, hormones, and amphenone on steroids in adrenal carcinoma. Science 124: 487-489, 1956.

4. HERTZ, R .; ALLEN, M. J .; TULLNER, W. W., and WESTFALL, B. B .: Surgical anesthesia in rabbit and dog with intravenous amphenone B. Proc. Soc. Exper. Biol. & Med. 79: 42-43, 1952.

5. HERTZ, R .; PITTMAN, J. A., and GRAFF, M. M .: Amphenone; toxicity and effects on adrenal and thy- riod function in man. J. Clin. Endocrinol, & Metab. 16: 705-723, 1956.

6. HERTZ, R .; RENOLD, A. E .; REDDY, W. J .; PITTMAN, J. A .; GRAFF, M. M., and THORN, G. W .: Pharmacologi- cal alteration of adrenalcortical function in man; amphenone and related compounds. Tr. A. Am. Physi- cians 69: 239-254, 1956.

7. HERTZ, R .; TULLNER, W. W .; SCHRICKER, J. A .; DHYSE, F. G., and HALLMAN, I., F .: Studies on amphe- none and related compounds. Recent Progr. Hormone Research 11: 119-147, 1955.

8. JAILER, J. W .; GOLD, J. J., and WALLACE, E. Z .: Evaluation of “cortisone test” as diagnostic aid in differentiating adrenal hyperplasia from adrenal neo- plasia. Am. J. Med. 16: 340-345, 1954.

9. LIDDLE, G. W .; COPPAGE, W. S .; GREENE, R. G., and ISLAND, D .: New tool in diagnostic evaluation of Cush- ing’s syndromc. Clin. Research Proc. 5: 106, 1957.

10. LIDDLE, G. W., et al. Personal communication.

11. PETERSON, R. E .; WYNGAARDEN, J. B .; GUERRA, S. L .; BRODIE, B. B., and BUNIM, J. J .: Physiological disposition and metabolic fate of hydrocortisone in man. J. Clin. Invest. 34: 1779-1794, 1955.

12. PLOTZ, C. M .; KNOWLTON, A. I., and RAGAN, C .: Natural history of Cushing’s syndrome. Am. J. Med. 13: 597-614, 1952.

13. RAPAPORT, E .; GOLDBERG, M. B .; GORDAN, G. S., and HINMAN, F., JR .: Mortality in surgically treated adrenocortical tumors; II, review of cases reported for 20 year period 1930-1949, inclusive. Postgrad. Med. 11: 325-353, 1952.

14. RENOLD, A. E .; CRABBE, J .; HERNANDO-AVENDANO, L .; NELSON, D. H .; Ross, E. J .; EMERSON, K., JR., and THORN, G. W .: Inhibition of aldosterone secretion by amphenone in man. New England J. Med. 256: 16-21, 1957.

15. SILBER, R. H., and PORTER, C. C .: Determination of 17, 21-dihydroxy-20-ketosteroids in urine and plasma. J. Biol. Chem. 210: 923-932, 1954.

16. THORN, G. W .; RENOLD, A. E .; GOLDFIEN, A .; NEL- SON, D. H .; REDDY, W. J., and HERTZ, R .: Inhibition of corticosteroid secretion by amphenone in patient with adrenocortical carcinoma. New England J. Med. 254: 547-551, 1956.

17. TULLNER, W. W .; GRAFF, M. M., and HERTZ, R .: Amphenone inhibition of adrenal corticosteroid output in hypophysectomized dog. Endocrinology 58: 802-807, 1956.

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