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1172/JCI102438
The adrenogenital syndrome associated with on the Metabolic Ward. The diet and fluid intake were
congenital adrenal hyperplasia (1) is in many kept constant throughout each study. Stools were col-
of its aspects the direct opposite of the other lected in six day periods, and urines in one to six day
pools. Stools and diets were analyzed for N, P, Ca, K,
syndrome which may result from adrenal hyper- Na, and Mg,5 and urines for these constituents and for
plasia, namely, Cushing's syndrome (2). For Cl, "reducing steroids," and 17-ketosteroids. Fasting
example, the former is characterized by rapid blood for determination of circulating eosinophils, and of
growth before epiphyseal closure, and an increase serum glucose, Ca, P, Mg,5 Na, K, Cl, and CO2 was
in strength, muscle mass, and skin thickness, drawn at appropriate intervals. The following methods
were used: Magnesium-Briggs (8); reducing steroids-
whereas the latter is characterized by cessation of Talbot and his associates (9) and Heard, Sobel and Venn-
growth before epiphyseal closure, and a decrease ing (10); eosinophil counts- Hills, Forsham and Finch
in strength, muscle mass and skin thickness. (11), except that the blood was diluted 1: 10 instead of
Since the effect of adrenocorticotropic hor- 1: 20; the remaining determinations-as described else-
mone (ACTH) in subjects with normal adrenals where (12).
is essentially to produce a temporary "Cushing's CASE HISTORIES
syndrome medicamentosa" (3-7) it was of interest C. O., M.G.H. No. 169, 536, was a 13 year old girl who
to observe the effects of ACTH in the adreno- had been seen first at the age of five because of the pres-
genital syndrome. The first part of this report ence of pubic hair since the age of two. Growth pro-
concerns the effects of ACTH in three female pa- ceeded rapidly, with markedly advanced bone age, and
tients with the adrenogenital syndrome. ceased by the age of nine with epiphyseal closure.
Menses had not appeared.
The results, which were surprising, led to the Physical examination revealed an abnormally muscu-
supposition that cortisone might inhibit the exces- lar girl, a height and span both of 57h inches, a large
sive production of androgens in these patients. thyroid cartilage, a deep voice, temporal recession of the
The second part of this report concerns the ef- hairline, hirsutism of face and body, a large amount of
fects of cortisone in two female patients with the pubic and axillary hair, scant breast tissue, a very large
clitoris, absent labia minora, and a common external ori-
adrenogenital syndrome. fice of urethra and vagina. X-rays revealed no adrenal
METHOD
tumor after air insufflation, and a normal skull. Re-
peated chemical analyses revealed normal serum glucose,
With the exception of the long-term studies which are Na, Cl, K, Ca, P, CO2 content, and alkaline phosphatase.
still in progress (vide infra) all studies were carried out A Cutler-Power-Wilder test revealed a normal four hour
1 Reported in part at the Proceedings of American So- chloride excretion. Twenty-four hour urine specimens
ciety for Clinical Investigation, May 1, 1950. (J. Clin. contained normal amounts of reducing steroids, sub-
Invest., 1950, 29, 797.) normal amounts (less than 2.8 mouse units) of "cortin"
2 The expense of these studies was defrayed by a grant (13), and very large amounts (60 to 70 mg.) of 17-
from the Rockefeller Foundation, a grant from Ayerst, ketosteroids.
McKenna and Harrison, Ltd., and grants from the Ameri- An electroencephalogram was read by Dr. John Abbott
can Cancer Society. A bed supported by Mr. Edward as follows: "This is an abnormal record for her age. It
Mallinckrodt, Jr., on the Metabolic Ward was used for shows a mild, diffuse, slow-wave cerebral dysrhythmia
these studies. (many six per second waves). Voltages are slightly
8 Surgeon, U.S.P.H.S., National Heart Institute. higher on the right."
'National Research Council Fellow in the Medical T. McH., M.G.H. No. 586, 528, was a ten year old girl
Sciences, 1949-1951. 5 Not done on patient C. 0.
237
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CO W=6 FEMALE AG 13
ADENO-GENITAL SYNDROME
3/31/4?
marked in the occipitoparietal region a little to the right had been tried without appreciable effect on the virilism.
of the midline. There are traces of normal alpha ac- Physical examination revealed a well-developed girl,
tivity at eight per second and 50 micro-volts." a height and span both of 62 inches, a slightly enlarged
On explorations by Doctor Oliver Cope, the internal thyroid cartilage, a moderately deep voice, slight temporal
genitalia were found to be of the normal female structure; recession of the hairline, hirsutism of the upper lip and
ovarian biopsy revealed developing follicles; the right body, large amounts of pubic and axillary hair, a moder-
adrenal gland was not grossly abnormal to palpation; and ate amount of breast tissue (estrogen therapy), a very
the left adrenal cortex showed hypertrophy on biopsy. large clitoris, absent labia minora, and a common ex-
R. H., M.G.H. No. 401, 611, was a 12 year old girl ternal orifice of urethra and vagina. X-rays revealed
who had been seen first at the age of five because of the normally placed kidneys and a normal skull. Repeated
presence of an enlarged clitoris since the age of three chemical analyses revealed normal serum glucose, Na,
months and pubic hair since the age of four. Growth pro- Cl, K, Ca, P, C02 content, and alkaline phosphatase.
ceeded rapidly, with advanced bone age, and ceased by Twenty-four hour urine specimens contained normal
amounts of reducing steroids and large amounts (17 to
the age of nine with epiphyseal closure. Menses had not
25 mg.) of 17-ketosteroids.
appeared, even on withdrawal of estrogen therapy, which Four electroencephalograms were read by Dr. John
Abbott as follows: "These are abnormal records for her
C.O. FEMALE MG 24 HR. age. They show a diffuse, slow-wave, cerebral dysrhy-
169536 AGE13
A.-G.S. ] ACTH thmia (four to six per second waves). The abnormality
3/3/47 37
is somewhat more marked on the left. There is some
normal alpha activity at around eight to nine per second
and 40 micro-volts."
10.
ACTH
I.
-i
4C
hi
I.-
z
4
-
;SERUM z:---
C - -
,FEC CA C I I
_UR I +
I
LtI4ARY CA lox
,g4.
026
e a l o 1 - .
IS IS I1
20 22 24 26 26
DM DAYS
FIG. 4. N, P, AND CA BALANCES, URINARY CA, SERUM P, CA AND DIFFUSIBLE CA DURING ADMINISTRATION OF ACTH
AND CORTISONE TO T. McH., A TEN YEAR OLD FEMALE WITH THE ADRENOGENITAL SYNDROME
The determinations of diffusible Ca in this and the subsequent experiments were done for us by Dr. John Dawson.
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3/6/49 566526
321
241
161
To :1
4
DAyS 3.
1.I
2~~~~~~ I
INTERVA
KG.
so$ 60.5
$5 0
54, 60.0
54D 59.5
535.
53
59.0
u
565
St 0
S#O 68.0o
OI 57.5
0 2 4 6 S 10
DAYS
FIG. 6. URINARY 17-KETOSTROIDS AND "REDUCING STEROIDS," ACTUAL AND THEORETICAL WEIGHT BASED ON N, NA,
AND K DURING EXPERIMENT SHOWN IN FIGURE 4
The upper limit of normal for reducing steroids by this method is 5 mg. per 24 hours.
4.01 0 -->0 1 o-
-
11.0 A'c
K1 0J - -
RUM
-
9.0J
4.01
GM/24 HR.
0
URINARY CA
Ght/24 HR.
0.08
0.4
OD8| z ~~ ~ ~ ~ ~ ~
601 -
0 2 4 6 8 10 12 14 16 IS 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60
DAYS
FIG. 7. N, P, AND CA BALANCES, URINARY CA AND SERUM P, CA, AND DIFFUSIBLE CA
AND GLUCOSE DURING ADMINISTRATION OF ACTH AND CORTISONE TO R. H., A 12 YEAR OLD
FEMALE WITH THE ADRENOGENITAL SYNDROME
3, 6, and 9). This result is in striking contrast to remain there with comparable doses of ACTH in
the elevations of urinary reducing steroids of two patients with essentially normal adreno-cortical
to ten times the normal values which have been function.
consistently reported following similar doses of
ACTH (3, 4, 6, 15). j) Glycosuria
No patient developed glycosuria at any time
i) Circulating eosinophils during therapy.
The initial counts of fasting eosinophils were
high in the two patients (T. McH. and R. H.) in Summary of results of ACTH therapy
whom they were done. With ACTH (Figure 12) In many respects, these patients responded ab-
there was a transient fall, followed by a rise to or normally to ACTH. The failure to increase sig-
above the initial values, despite continued ACTH nificantly the excretion of reducing steroids, to
therapy. This observation is in contrast to the develop a negative N balance, or to show a large
well-documented observation (3-6) that the cir- and sustained fall of circulating eosinophils is an
culating eosinophils fall to approximately zero and indication that the output of "carbohydrate-active"
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:JL
'OJL ~~~~~~~(H-7210)
- -_SERUMK - _
jtdQ le4M4NR .\N.
1 .
_ I
02 4 6 8 l0 12 14 16 182
Ito 4 26 2 30 32 34 36 3 40 44 464 62 "
4 0
FIG. 8. K, NA, AND MG BALANCES, URINARY CL, SERUM K, NA, CL, CO2 CONTENT, AND MG,
AND PLASMA PH DURING THE EXPERIMENT SHOWN IN FIGURE 7
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quently, cortisone acetate was administered in use of cortisone at this dosage in patients with
doses of 100 mg. a day for 12 days to patients other syndromes. Sprague and his co-workers
T. McH. and R. H. state, "As a rule, the augmentation of nitrogen
excretion was slight or absent when the dose of
II. Cortisone cortisone was 100 mg. daily."
The metabolic effects of cortisone are shown in The second striking result of cortisone therapy
Figures 4-9. The changes in P, Ca, K, Na, and was the marked progressive fall in 17-ketosteroid
Cl metabolism and in excretion of reducing steroids excretion in both patients (Figures 6 and 9). The
are not remarkable, and do not differ essentially urinary 17-ketosteroids remained low for eight
from those previously reported (6) following the (R. H.) and 12 (T. McH.) days, then rose gradu-
use of cortisone acetate at similar dosages. There ally to the pre-injection levels. A similar depres-
was a slight fall of urinary Mg in both patients. sion of 17-ketosteroids with cortisone in a pa-
Cortisone produced a rise in urinary N in both tient with the adrenogenital syndrome has been re-
patients, resulting in a markedly negative N bal-
ance in T. McH. (Figure 4) and increasing the ported by Wilkins and his colleagues (23).
already existing negative N balance in R. H. (Fig- III. ACTH and Cortisone
ure 7). This result is contrary to those of
Sprague and associates (6), Clark, Ropes and As stated above, we had believed, a priori, that
Bauer (21), and ourselves (22), following the the effect of cortisone would be to lower the uri-
RX FEMALE AGE
AORDNAL-GETALi
3/14/5O 401611
MGJ24HR.
68
60
72
64
56
111
48
40
32
24
16
8i
MG.124 .
KG.
47.5 ^
47.0
46.5
46.0
45.5.
45.0 TH
44.5 AC
44.
435
43.
42.5
42.0
0 2 4 6 8 10 It 14 161 224
tO 26 30 3 34 38 40 4244
" 4 0 5 54 ss0
DM
FIG. 9. URINARY 17-KEToSTmOIDS, "REDUCING STERoms," ACTUAL WEIGHT, AND THEO-
RETICAL WEIGHT BASE ON N, NA, AND K DURING EXPERIMENT SHOWN IN FIGURE 7
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16
Consideration of the adrenogenital syndrome,
which may be associated with either hyperplasia
14 200 or tumor of the adrenal cortex, leaves little doubt
12
that the adrenal cortex may produce steroids
10 . which have virilizing properties. There is con-
8 _YXEDEMA{
M siderable circumstantial evidence (2) that the
6 0 T.MCH.() measurement of urinary 17-ketosteroids provides
4 an index of the quantities of such steroids being
2 * C.Q produced. Further, there is clinical evidence (2)
O * that these steroids may have somatotropic, nitro-
-2
gen-retaining, as well as virilizing properties.
-4
The present study provides two pieces of indi-
-6
rect evidence in support of the latter point. In the
first place, when T. McH. received 200 mg. of
-8
ACTH a day, there was a marked rise in 17-
-10
ketosteroid excretion without a significant rise in
-12 * TMOH.(2) urinary reducing steroids. Under these circum-
NITROGEN EXCRETION 6-DAYS ACTH stances, nitrogen retention was increased.7 Ni-
FIG. 10. THE TOTAL N ExCRETION DURING THE FIRST trogen retention with ACTH has not heretofore
Six DAYS OF ACTH ADMINISTRATION TO THE THREE been described, presumably because nitrogen loss
PATIENTS REPORTED, CONTRASTED WITH THAT IN 11 COM-
PARABLE EXPERIMENTS ON PATIENTS WITH ESSENTIALLY
with "sugar" hormone outweighs any nitrogen
NORMAL ADRENAL CORTICAL FUNCTION, AND ONE ON A retention due to somatotropic hormones. In the
PATIENT WITH MYXEDEMA second place, when T. McH. and R. H. received
Nitrogen excretions were calculated as deviations from 100 mg. of cortisone a day there was a marked
the average of control values. Note decreased N ex-
cretion in patients with the adrenogenital syndrome, and
fall in 17-ketosteroid excretion. Under these cir-
actual N retention with 200 mg. of ACTH in T. McH. cumstances, more loss of N was produced than
(2). has been observed following this dosage8 of
cortisone. Thus in the first instance, with a rise
nary 17-ketosteroid excretion by depressing pitui- of adrenal androgen unopposed by adrenal "sugar"
tary ACTH production, and not by direct action hormone there was N retention, whereas in the
on the adrenal gland. To provide further evidence second instance, with a fall of adrenal androgen
on this point we decided to administer ACTH and there was an abnormally great N loss following
cortisone together to patient R. H. If cortisone exogenous "sugar" hormone.
has a direct action on the adrenal cortex it should
T N retention did not occur in R. H. in spite of a greater
decrease the response to administered ACTH.
The results show that the rise in 17-ketosteroid rise in 17-ketosteroid excretion. This may be a result
of qualitative differences in the precursors of the 17-
excretion resulting from ACTH together with ketosteroids in these two patients (13, 24).
cortisone (Figure 9, days 53 through 60) did not 8 Either on an absolute or a mg. per kg. basis.
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EEASCT
H
MEQ.24 HR.
- 60
- 54
Ik
-48
-42
- 36
- 30-
URINAURY POTASSIUM
- 24
- 18 DI)EV. FROM AV. OF CONTROL DATA
- 12
- 6
0- 8C.o.
+6 -T McH (0
fT.McKw
+ 12 'RH
+ Is
+ 24
+ 30
+ 36
+ 42
+ 48
+ 54
6 5 4 3 0 ! 2 3 4
FIG. 11. THE URINARY K EXCRETION DURING THE FIRST FOUR DAYS OF, AND THE FIRST FOUR
DAYS AFTER, ADMINISTRATION OF ACTH TO THE PATIENTS REPORTED CONTRASTED WITH THAT
IN 11 COMPARABLE EXPERIMENTS ON PATIENTS WITH ESSENTIALLY NORMAL ADRENAL CORTICAL
FUNCTION
The shaded area is that covered by two standard deviations above and below the mean normal
curve (heavy black line). Note that patients with the adrenogenital syndrome did not show
the K diuresis on starting nor the K retention on stopping ACTH.
17 KETO-
COATICODS STEROIDS
ACRENO-GENlTAL
NORMAL ADRENO -GENITAL WITH EZ
eosinophils are not depressed. One patient is vations on the physiologic effects of cortisone and
having monthly periods with cramps. ACTH in man. Arch. Int. Med., 1950, 85, 199.
7. The above findings suggest that this syn- 7. Bartter, F. C., Fourman, P., Albright, F., Forbes,
drome involves a primary defect of the adrenal A. P., Jefferies, W. McK., Griswold, G., Dempsey,
E., Bryant, D., and Carroll, E., The effect of
cortex, and a secondary increase of pituitary adrenocorticotropic hormone in panhypopituitarism.
ACTH production. J. Clin. Invest., 1950, 29, 950.
8. In all patients the electroencephalograms 8. Briggs, A. P., Some applications for the colorimetric
showed asymmetry, elevation of voltages, and ab- phosphate method. J. Biol. Chem., 1924, 59, 255.
normal slow waves. This finding is unexplained. 9. Talbot, N. B., Saltzman, A. H., Wixom, R. L., and
Wolfe, J. K., The colorimetric assay of urinary
corticosteroid-like substances. J. Biol. Chem., 1945,
REFERENCES 160, 535.
1. Blackman, S. S., Jr., Concerning the function and 10. Heard, R. D. H., Sobel, H., and Venning, E. H.,
origin of the reticular zone of the adrenal cortex; The neutral lipide-soluble reducing substances of
hyperplasia in the adrenogenital syndrome. Bull. urine as an index of adrenal cortical function. J.
Johns Hopkins Hosp., 1946, 78, 180. Biol. Chem., 1946, 165, 699.
2. Albright, F., Cushing's syndrome. Harvey Lectures, 11. Hills, A. G., Forsham, P. H., and Finch, C. A.,
1942-3, 38, 123. Changes in circulating leukocytes induced by the
3. Forsham, P. H., Thorn, G. W., Prunty, F. T. G., and administration of pituitary adrenocorticotropic hor-
Hills, A. G., Clinical studies with pituitary adreno- mone in man. Blood, 1948, 3, 755.
corticotropin. J. Clin. Endocrinol., 1948, 8, 15. 12. Reifenstein, E. C., Jr., Albright, F., and Wells, S. L.,
4. Conn, J. W., Louis, L. H., and Johnston, M. W., The accumulation, interpretation, and presentation
Metabolism of uric-acid, glutathione, and nitrogen, of data pertaining to metabolic balances, notably
and excretion of 11-oxysteroids and 17-ketosteroids those of calcium, phosphorus, and nitrogen. J.
during induction of diabetes in man with adreno- Clin. Endocrinol., 1945, 5, 367.
corticotropic hormone. J. Lab. & Clin. Med., 1949, 13. Talbot, N. B., ZygmuntowiLl, A. N., Wood, M., and
34, 255. Christo, E., Observations on adrenal cortical
5. Conn, J. W., Louis, L. H., and Wheeler, C. E., Pro- "sugar-fat-nitrogen" hormone ("11-17-OCS") and
duction of temporary diabetes mellitus in man with "17-ketosteroid precursor" production by normal
pituitary adrenocorticotropic hormone; relation to and abnormal individuals of various ages with com-
uric acid metabolism. J. Lab. & Clin. Med., 1948, ments on the fact that (a) there may be two
33, 651. ACTH's and (b) the normal adrenal cortex may
6. Sprague, R. G., Power, M. H., Mason, H. L., Al- not produce true androgens, in Proceedings of the
bert, A., Mathieson, D. R., Hench, P. H., Kendall, First Clinical ACTH Conference, John R. Mote,
E. C., Slocumb, C. H., and Polley, H. F., Obser- Editor. Blakiston Co., Philadelphia, 1950, p. 32.
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ERRATUM
In Table VII of the article entitled "Acetylation Studies in Hu-
man Subjects with Metabolic Disorders," by H. Gershberg and
W. J. Kuhl, Jr., in the December 1950 issue (pp. 1625-1632), the
values for both total and free serum cholesterol are mgm. per cent
rather than as erroneously given.