URINARY STEROIDS IN ADRENOCORTICAL TUMOR
EXCRETION OF CORTICOIDS AND 17-KETOSTEROIDS ON ADMISSION, AFTER ACTH, FOLLOWING RESECTION, AFTER WITHDRAWAL OF ACTH, AND UPON RECURRENCE OF MASCULINIZING CARCINOMA*
JAMES D. HARDY, M.D., F.A.C.S.
MEMPHIS, TENN.
FROM THE DEPARTMENT OF SURGERY AND SURGICAL LABORATORIES, MEDICAL COLLEGE OF THE UNIVERSITY OF TENNESSEE, MEMPHIS
THE SURGICAL MANAGEMENT of function- ing tumors of the adrenal cortex continues to present many problems. The purpose of this report is to record urinary steroid ex- cretion data which bear upon the following questions :
1. What is the relative preponderance of urinary 17-ketosteroids over urinary cor- ticoids in a patient whose masculinizing tumor has produced the adrenogenital syn- drome, in contradistinction to the prepon- derance of corticoids over 17-ketosteroids in the patient whose tumor has produced the picture of Cushing’s syndrome?
2. Does the preoperative administration of ACTH increase the secretory activity of the tumor?
3. Following resection of the tumor, what interval is required for the excretion or the utilization of the excessive deposits of steroids stored in the tissues? What is the relationship between this interval and the time of development of postoperative adrenal crisis?
4. Does the administration of exogenous ACTH suppress the elaboration of endo- genous ACTH by the patient’s own pitui- tary?
5. Are steroid excretion studies of value in the subsequent management of a patient whose functioning tumor has been resected?
The data to be presented were obtained from the study of a 28-year-old medical secretary who, over a period of 18 months, had developed an increased growth of hair on the face and around the nipples, a male type pubic hair distribution, enlargement of the clitoris, inability to sing high notes in church, and amenorrhea. She was proved to have a functioning carcinoma of the right adrenal cortex.t The urinary corti- coids were measured by a modification of the method of Heard and Sobel” (corti- coids are adrenal steroid fractions which are considered to be derived from 11-oxy- steroids such as cortisone) and the total neutral 17-ketosteroids were measured by the procedure outlined by Robbie and Gibson.3
URINARY EXCRETION OF 17-KETOSTEROIDS AND CORTICOIDS ON ADMISSION
Seventeen-ketosteroids. The tumor was one which was secreting enormous amounts of androgenic steroids, excreted in the urine as 17-ketosteroids (Table I, Fig. 1). On admission the patient was excreting 280 mg. of 17-ketosteroids each 24 hours (average normal, 10 mg./24 hours). This finding firmly established the identity of the right upper quadrant mass in the ab- domen, and it explained the masculiniza- tion which had occurred in the preceding months.
* These studies were aided by grants from The Damon Runyon Memorial Fund and The American Cancer Society. Submitted for publica- tion February, 1953.
t The clinical aspects of this case are reported in detail elsewhere.
Corticoids. As is frequently the case, this tumor was secreting increased amounts not only of androgenic substances, but also of corticoids (11-oxysteroids, 21-carbon atom compounds such as A, B, C, D, E, and F). In Figure 2 and in Table I it is seen that the patient was excreting 30
whereas in the male the testes provide an additional source of these steroids.
Does ACTH increase the secretory activ- ity of the tumor?
In Figures 1 and 2 and in Table I it may be seen that when a dose of 25 mg. of ACTH was administered intramuscularly
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-
AB FUNCTIONING ADRENOCORTICAL CARCINOMA URINARY EXCRETION OF 17-KETOSTEROIDS BEFORE RESECTION, AFTER RESECTION, AND UPON RECURRENCE OF TUMOR
4
mg
12
24N
10
8
25 mg/ 6 h.
200 mg
RECURRENCE
6
CORTISONE
ACTH RESTARTED
4
ACTH
CCTH
ACTH
ACTH STOPPED
2
CON TISÔME
I
2
3
4
5
6
8
9
12
13
4
5
16
17
19
20
21
22
-
MAY 20
De
DAYS
SEPT 12
mg. of these substances each 24 hours (normal for laboratory, 5 to 8). Thus, one might have anticipated a mixed type of clinical and physiologic picture to accord with the mixed pattern of increased steroid excretion found in the urine. Actually, however, so great was the preponderance of the increased androgen production over the increased corticoid production that her physical changes were almost entirely those produced by androgenic steroids, of which testosterone is an example. In the female, the adrenal cortex is ordinarily the only source of androgenic substances,
AB FUNCTIONING ADRENOCORTICAL CARCINOMA URINARY EXCRETION OF CORTICOIDS DEFORE PE SECTION, AFTER MESECTION AND JHON RECURRENT OF TUMOR
16
14
mg
12
24hr
10
8
25 mg/6 h
6
200m
ACTH RESTARTED
CORTISONE STOPPED
ACTH STOPPED
4
AC TH
ACTH
ACTH
2
!
2
3
4
5
6
1
8
9
10
12
13
14
15
16
17
18
19
20
21
22
MAY 20
DAYS
SEPT 42
every six hours, beginning three days pre- ceding the operation, the urinary excretion of 17-ketosteroids promptly increased from the previous level of 280 mg. to 415 mg. per 24 hours. Yet, the urinary excre- tion of corticoids-the steroids most effica- cious in preventing adrenal crisis-was not affected. Thus, while the administration of ACTH may increase the secretory activity of a functioning adrenal tumor, it will not
Volume 138 Number 5
necessarily increase the production of cor- ticoids, if the tumor happens to be one which is specializing in the secretion of androgens. In this situation the preoper- ative administration of ACTH would ap- pear to be of little value in saturating the
| Corticoids mg./24 hrs. | mg./24 hrs 17-ketos- teroids | ||
|---|---|---|---|
| On admission | 5-2 .- 52 | 31.4 | 280.0 |
| 5-21-52 | 30.0 | 276.0 | |
| 5-22-52 | 33.3 | 280.0 | |
| ACTH begun | 5-23-52 | 26.4 | 280.0 |
| 5-24-52 | 31.8 | 415.0 | |
| 5-25-52 | 30.7 | 380.0 | |
| Operation (ACTH stopped) | 5-26-52 | 8.9 | 33.2 |
| 5-27-52 | 6.8 | 11.4 | |
| ACTH restarted | 5-28-52 | 9.4 | 8.4 |
| 5-29-52 | 10.4 | 7.0 | |
| 5-30-52 | 15.3 | 6.6 | |
| 5-31-52 | 11.2 | 6.7 | |
| 6- 1-52 | 7.4 | 5.8 | |
| 6- 2-52 | 10.6 | 7.2 | |
| 6- 3-52 | 9.5 | 5.3 | |
| 6- 4-52 | 3.1 | 5.4 | |
| 6- 5-52 | 16.1 | 5.1 | |
| ACTH stopped | 6- 6-52 | 7.0 | 3.6 |
| 6- 7-52 | 6.2 | 3.3 | |
| 6- 8-52 | 4.7 | 2.7 | |
| 6- 9-52 | 8.9 | 4.0 | |
| 6-10-52 | 7.9 | 4.0 | |
| Recurrence of tumor | 9-12-52 | 21.9 | 105.0 |
tissues with 11-oxysteroids, to diminish the likelihood of adrenal crisis following resection of the tumor. Fortunately, the removal of functioning adrenal tumors whose increased steroid secretion is pre- dominately androgenic is less likely to be followed by adrenal crisis than is the re- moval of a functioning tumor whose in- creased steroid production predominantly affects the corticoids.
What interval is required for the desat- uration of the body tissues of steroids postoperatively?
It has often been observed clinically that if adrenal crisis is to occur, following the removal of a functioning adrenocortical
tumor, the signs of adrenal failure will be manifest within from 48 to 72 hours follow- ing operation. In Figures 1 and 2 it may be observed that the urinary excretion of both corticoids and 17-ketosteroids fell to a nor- mal level within 48 hours following the operation, despite the very high level of 17-ketosteroid excretion which had been present immediately before operation. The administration of 50 mg. of cortisone intra- muscularly every six hours does not con- sistently elevate the urinary excretion of corticoids in normal subjects1 and this dosage did not appear materially to affect the excretion of this moiety in Patient A. B. (Fig. 2). Thus, the clinical and the labo- ratory findings are in agreement with re- spect to the time relationships which at- tend postoperative adrenal crisis.
Does the injection of exogenous ACTH suppress the elaboration of endogenous ACTH by the patient’s own pituitary?
The thesis has often been advanced that the administration of ACTH in effective doses does in fact result in a suppression of the usual activity of the patient’s pitui- tary in elaborating ACTH, and that in pa- tients so treated there may exist a tempo- rary period of relative adrenocortical in- sufficiency following the withdrawal of the exogenous ACTH. Table I and Figures 1 and 2 would appear to offer evidence which supports this hypothesis. It may be seen that following the withdrawal of ACTH on the tenth postoperative day (the seventeenth day of observation) the level of excretion of both corticoids and 17- ketosteroids fell progressively for three days, following which both levels returned simultaneously to relatively normal values. True, these changes were not great if ex- pressed in absolute values, but they were substantial when expressed on a percent- age basis. Further, these changes were no greater than certain random variations on previous days. However, the timing and the uniformity of the downward trend
would appear to be significant. The fact that the levels of excretion of both these fractions of the adrenocortical secretion varied in the same direction at the same time would appear to suggest that pituitary activity was diminished by the administra- tion of ACTH and/or cortisone.
Are steroid excretion studies of value in the detection of a recurrence of the adrenal tumor?
The patient had a fairly stormy 72 hours immediately following operation, despite vigorous supportive therapy. In the weeks that followed, however, her menses re- turned, her breasts again enlarged, and she felt quite well for almost five months. At this time she began to lose her appetite and to feel weak, but at first no organs or masses were definitely palpable. However, the urinary steroid excretion studies re- vealed that her corticoids had again risen to 21 mg. per 24 hours and her 17-ketoste- roids to 105 mg. per 24 hours. Several weeks later she died with hepatic metas- tases.
SUMMARY AND CONCLUSIONS
1. Detailed data are presented showing the urinary excretion of corticoids and 17- ketosteroids on admission, after the admin- istration of ACTH, following resection, after the withdrawal of ACTH, and upon the recurrence of the tumor in a patient with a masculinizing adrenocortical car- cinoma.
2. The tumor had produced physical changes compatible with those of the adrenogenital syndrome. This was in ac- cord with the fact that in the excessive secretion of steroids manifested by this particular tumor the production of andro- gens, excreted in the urine as 17-ketoster- oids, far outweighed the production of corticoids.
3. Adrenocorticotrophic hormone was administered preoperatively in an effort to utilize the secretory capacity of the tumor to diminish the likelihood of postoperative crisis. The secretion of 17-ketosteroids was sharply increased, but the secretion of cor- ticoids was not affected. Corticoids are the steroids which are most effective in pre- venting adrenal crisis following the resec- tion of a functioning adrenocortical tumor.
4. It has been observed clinically that if adrenal crisis is to occur following the re- section of a functioning adrenal tumor, the signs will become manifest during the first 48 to 72 hours. Data are presented which indicate that this is the amount of time re- quired for the tissues to become cleared of the excessive steroid deposits elaborated by the tumor.
5. Others have suggested that the sud- den withdrawal of an effective course of ACTH therapy may be followed tempo- rarily by a period of relative adrenocortical insufficiency, the result of suppression of the patient’s own pituitary by the exo- genous ACTH. Data are presented which suggest that this may in fact occur. Three days were required for the urinary excre- tion of corticoids and 17-ketosteroids to return to preexisting levels following the withdrawal of ACTH in the late postoper- ative period.
6. Steroid excretion studies may reveal the recurrence of a malignant adrenal tumor before evidence of such a recurrence is apparent on physical examination.
BIBLIOGRAPHY
1 Hardy, J. D .: The Effect of the Intramuscular Administration of Cortisone on the Urinary Excretion of Corticoids in Normal Subjects. Unpublished data.
2 Heard, R. D. H., and H. Sobel: A Colorimetric Method for the Estimation of Reducing Steroids. J. Biol. Chem., 165: 687, 1946.
3 Robbie, W. A., and R. B. Gibson: Rapid Clin. ical Determination of Urinary 17-ketosteroids J. Clin. Endocrinol., 3: 200, 1943.