of opinion about whether the full-fledged syndrome of hemochromatosis may be produced by therapeutic administration (oral or parenteral), it seems advis- able to avoid iron overload at least until the question is settled. Iron has no therapeutic value outside iron deficiency and may conceivably do harm. It must be remembered that for practical purposes iron is not excreted by the body. If one adheres to the use of 500 to 1000 mg. as a therapeutic trial and confirms the diagnosis in each case by awaiting at least a be- ginning response before continuing therapy, and if one gives no more than the calculated total dose, no problem of iron overload should arise. It seems advisable as well to obtain a history concerning pre- vious parenteral iron therapy, and whenever possible the diagnosis should be aided by the use of serum iron determinations or by evaluation of the bone-marrow iron.
SUMMARY AND CONCLUSIONS
Data are presented on the use of a new iron- dextran complex for parenteral (intramuscular) in- jection in 60 patients. The indications for parenteral
injection in preference to the oral route are discussed. It is concluded that this preparation is both effective and relatively nontoxic and can be recommended for use when the parenteral route is indicated.
We are indebted to Dr. Sanford Leiken, District of Columbia General Hospital, for some of the serum iron determinations.
REFERENCES
1. Brown, E. B., and Moore, C. V. Parenterally administered iron in treatment of hypochromic anemia. Progr. Hemat. 1:22-46, 1956.
2. Martin, L. E., et al. Pharmacology of iron-dextran intramuscular haematinic. Brit. J. Pharmacol. 10:375-382, 1955.
3. Baird, I. M., and Podmore, D. A. Intramuscular iron therapy in iron-deficiency anaemia. Lancet 2:942-946, 1954.
4. Rath, C. E., and Finch, C. A. Sternal marrow hemosiderin: method for determination of available iron stores in man. J. Lab. & Clin. Med. 33:81-86, 1948.
5. Ramsay, W. N. Determination of iron in blood plasma or serum. Biochem. J. 53:227-231, 1953.
6. Idem. Improved technique for determination of plasma iron. Bio- chem. J. $7: (Proceedings Biochemical Society) XVII, 1954.
7. Rath, C. E., and Finch, C. A. Chemical, clinical, and immuno- logical studies on products of human plasma fractionation. XXXVIII. Serum iron transport: measurement of iron-binding capacity of serum in man. J. Clin. Investigation 28:79-85, 1949.
8. Ventura, S. Determination of unsaturated iron-binding capacity of serum. J. Clin. Path. 5:271-274, 1952.
9. Brecher, G., and Schneiderman, M. A. Time-saving device for counting of reticulocytes. Am. J. Clin. Path. 20:1079-1083, 1950.
10. Brecher, G. New methylene blue as reticulocyte stain. Am. J. Clin. Path. 19:895, 1949.
11. Coleman, D. H., Stevens, A. R., Jr., and Finch, C. A. Treat- ment of iron deficiency anemia. Blood 10:567-581, 1955.
DOES ADRENOCORTICAL HYPERPLASIA RESULT IN ADRENOCORTICAL CARCINOMA ?*
GEORGE J. HAMWI, M.D., M.S.,; RICHARD A. SERBIN, M.D.,# AND FRED A. KRUGER, M.D.§ COLUMBUS, OHIO
O NLY 72 cases of masculinizing tumors of the adrenal cortex were reported in a recent twenty- year survey.1 In the case reported below, symptoms of masculinization were present for thirty years before the removal of an adrenocortical carcinoma. There was responsiveness both to stimulation by ACTH and to inhibition by adrenal corticoids. Both the duration of illness and behavior are exceedingly unusual for such a lesion, although they are not without precedent.
CASE REPORT
A 39-year-old colored woman was transferred to Ohio State University Hospital from another hospital on January 18, 1957, for evaluation of the possibility of an adrenal tumor with virilism. The patient estimated the onset of her present illness to about the age of 9 or 10 when chest hair, deepening of the voice and a beard requiring daily shaving began to develop. As well as she could remember, she had been normal in development until this time but had ceased growing at this age, when she was 150 cm. tall. She was not aware of hypertrophy of the clitoris before this age, but did notice it subsequently. She had never menstruated.
*From the Division of Endocrinology and Metabolism, Ohio State University Health Center.
Associate professor of medicine, Ohio State University College of Medicine; chief, Division of Endocrinology and Metabolism, University Hospital.
Instructor in medicine, Ohio State University College of Medicine; resident in medicine, University Hospital.
§Assistant professor of medicine, Ohio State University College of Medicine.
At the age of seventeen, determination of urinary excretion of 17-ketosteroids at another institution showed levels as high as 83.2 mg. in 24 hours. Dilatation and curettage were done, and perirenal air insufflation attempted. No abnormalities were found. The final diagnoses were hypo- plasia of the pelvic organs, hirsutism, hypertrophy of the glans clitoris, chronic vaginitis and chronic cervicitis. After clitorectomy, the patient was advised to take 1 mg. of stilbestrol daily. She had 1 episode of vaginal bleeding for 2 days after discharge but had had none since. Since that time temporal balding had developed but she had been in excellent health and quite vigorous and active. She was married and stated that she enjoyed normal sexual relations. She had recently been admitted to another institution be- cause of emotional difficulties, in part generated by her masculinized state.
Physical examination revealed a short, stocky, muscular woman with a body configuration more typical of the male than of the female. She was 150 cm. tall, with a span of 155 cm .; the distance from crown to symphysis was 76 cm., and that from symphysis to floor 74 cm. The weight was 60.8 kg. (134 pounds). There was definite hirsutism, with a beard, male distribution of hair on the chest, back, neck, legs and abdomen, and temporal balding; however, there was a characteristic female escutcheon (Fig. 1). The head, neck, lungs, heart and abdomen were all within normal limits. The breasts were small, but acinar tissue could be palpated. Pelvic examination revealed absence of the labia minora and a very small uterus. The adnexal structures could not be felt.
The blood pressure was 138/88, and the pulse 92.
The 17-ketosteroid excretion was markedly elevated, ranging from 80 to 185 mg. per 24 hours. Upon adminis- tration of 9-alpha-fluorocortisol a considerable decrease - to between 40 and 50 mg. per 24 hours - resulted. After 25 mg. of ACTH intravenously over 200 mg. was excreted
in 24 hours. Plasma 17-hydroxycorticoids failed to increase under ACTH administration, the plasma level being 7.7 microgm. per 100 ml. before and 7.0 microgm. 6 hours after 25 mg. of ACTH given intravenously. Pregnantriol levels in the urine were consistently elevated, ranging from 11 to 60 mg. per 24 hours. Dehydroepiandrosterone was absent from the urine. These results were consistent with the usual concepts of behavior of virilizing adrenal hyperplasia. However, an intravenous pyelogram demonstrated a definite tumor mass in the region of the superior pole of the left kidney (Fig. 2). This was confirmed by presacral insufflation of carbon dioxide.
Routine laboratory data, including a serologic test, urinalysis and hemogram, were within normal limits. The basal metabolic rate was -3 per cent; the blood urea nitro- gen was 10 mg., the cholesterol 205 mg., and the inorganic phosphorus 3.7 mg. per 100 ml., and the alkaline phos- phatase was 11.3 S.J.R. units, and the serum amylase 86 units. An x-ray film of the chest and a bone survey gave no definite evidence of metastasis.
After the preliminary diagnostic studies the patient was operated upon .* Through a left paramedian incision and after mobilization of the descending colon, the retroperi- toneal space was entered. A tumor was found to encircle the kidney and was freed by blunt and sharp dissection. The multilobular tumor, weighing 228 gm., was delivered intact. The contralateral adrenal gland was atrophic, and no obvious metastases were noted. Frozen section was interpreted as showing adenocarcinoma. On cut section
*Operation performed by Dr. Edwin H. Ellison, professor of surgery, Ohio State University College of Medicine.
the adrenal gland was rather well outlined, and the tumor seemed to surround it completely. Microscopically, there was infiltration of a regional lymph node and muscle fat with large, dark-staining tumor cells. The nuclei showed variation in size, and some cells were multinucleated. The final microscopical interpretation was well differentiated adrenocortical carcinoma, invading fat and lymph node (Fig. 3 and 4).
The postoperative course was uneventful. The patient was maintained on 200 mg. of cortisone on the day of surgery and the 1st day thereafter. The dose of cortisone was decreased stepwise for 7 days to 25 mg. 3 times a day, after which she was given 9-alpha-fluorohydrocortisone,t 6 mg. daily.
After operation and during steroid therapy the 17-keto- steroid level returned to normal. Beginning on the 12th postoperative day, 40 units of ACTH gel was administered daily for 3 days, after which the 17-ketosteroid level rose from 10 to 106 mg. per 24 hours. No treatment was given for the following week, and the 17-ketosteroid level ranged from 39 to 104 mg. per 24 hours. This persistent elevation, although not as marked as that before operation, indicated either that tumor tissue was still present or that the residual adrenal gland was now reacting in a manner characteristic of adrenal hyperplasia. The patient has been on continuous suppressive therapy with prednisone, 5 mg. 3 times a day;
on this dose the 17-ketosteroid levels have been normal, ranging from 21 to 3 mg. per 24 hours. The therapy was discontinued for 1 week, with a rise in 17-ketosteroids to 50 mg. per 24 hours. The urinary excretion of pregnantriol generally paralleled that of the urinary 17-ketosteroids, ranging from 11 to 60 mg. per day (upper limit of normal, 1 mg. per 24 hours). 17-hydroxycorticoid levels were within normal limits, ranging between 5.1 and 20.0 mg. per day. Five months after operation there had been no significant objective or subjective change (Fig. 5).
¡Kindly supplied by Dr. Elmer Alpert, of Merck Sharp and Dohme, West Point, Pennsylvania.
DISCUSSION
The derangements in corticosteroid metabolism that are causally related to the genesis of the adreno- genital syndrome have been discussed in recent reviews by Bongiovanni and Eberlein2 and Reifenstein.3 Char- acteristic of this syndrome and distinguishing it from other virilizing disorders is the high level of urinary pregnantriol, which is normally present in only small amounts (1 mg. or less per twenty-four hours). Butler and Marrian4 first isolated this substance from the urine of patients with the adrenogenital syndrome, and others subsequently confirmed their observation, but it remained for Bongiovanni5 to recognize its diag- nostic importance and to devise a relatively simple laboratory procedure for its determination as an entity distinct from pregnanediol. The usual procedures for pregnanediol evaluation measure pregnantriol as well. For this reason the several references in the liter- ature to elevated pregnanediol excretion in masculiniz- ing syndromes need to be re-evaluated. The term “pregnanediol chromogens” has been used to denote substances measured by these less specific methods.
2 3 4 5 6 7 8 9 10 11 12
The significance of elevated pregnantriol excre- tion in the adrenogenital syndrome may be briefly outlined. The sequence involved in the biogenesis of cortisol from cholesterol in the adrenal cortex is gen- erally agreed to be as follows: cholesterol → pregneno- lone → progesterone → 17-hydroxyprogesterone → compound S → cortisol. In the more common variety of the syndrome there appears to be a block or defi- ciency in the 21-hydroxylating system that is necessary for the transformation of 17-hydroxyprogesterone to compound S. As a result 17-hydroxyprogesterone ac- cumulates and is secreted by the cortex and then
further metabolized in the peripheral tissues to preg- nantriol and other steroids, including certain 17-keto- steroids. In addition, the absence or deficiency of cortisol permits ACTH production in the pituitary gland to rise unchecked and stimulate the adrenal cortex to produce more 17-hydroxyprogesterone. Con- comitantly, adrenal androgen production is greatly enhanced, as evidenced by the elevated 17-ketosteroid excretion and development of virilizing symptoms.
A direct relation between 17-hydroxyprogesterone and the androgens remains to be established. To date the evidence appears to be against any direct androgenic effect of the former or of its extra- adrenally produced metabolites.6 That it may prove to be a precursor in the biosynthesis of adrenal andro- gens is a possibility. It is probable that the 11-oxy- genating enzyme system involved in the last step of the cholesterol → cortisol scheme is intact, since 11- oxyketosteroids are excreted in considerable amounts. Supporting this assumption is the observation of Zondek and Finkelstein7 that substantial amounts of pregnantriol-11-one characteristically appear in the urine of patients with the adrenogenital syndrome. These authors have determined it fluorometrically as an aid in the diagnosis of congenital adrenocortical hyperplasia.
Eberlein and Bongiovanni8 have described a much rarer variety of the adrenogenital syndrome of mas- culinization complicated by hypertension. In such cases the 11-oxygenating system is blocked, and com- pound S is the major secretory product. The urine of these patients contains no demonstrable 11-oxyketo- steroids (Fig. 6).
On the basis of the scheme described above, exoge- nous cortisol should act to compensate for the deficient adrenal secretion and suppress ACTH production. This, in turn, would be reflected by diminished adrenal secretion of androgens and abnormal steroids. The establishment of this fact by Wilkins9 is the basis
of present therapy for this type of virilism. Cortisone, cortisol and, more recently, synthetic glucocorticoids such as prednisone are all effective therapeutic agents in correcting the chemical abnormalities. The urinary 17-ketosteroid and pregnantriol levels, individually or together, afford a convenient means for judging the adequacy of dosage of these agents.
The plasma 17-hydroxycorticoid levels in this pa- tient were consistent with the usual findings in con-
URINARY 17 KETOSTEROIDS LEVELS EXPRESSED AS MILLIGRAMS PER DAY EXCRETION
CORTISONE
200
FLUOROHYDROCORTISONE 6 MG. Q.D.
100
PREDNISONE 5 GM. Q.D.
9
SURGERY 35%
ACTH 25U I.V.
200
ACTH GEL 40 MG.LM.
180
160
140
120
100
80
60
40
20
0
URINARY PREGNANTRIOL LEVEL EXPRESSED AS MILLIGRAMS PER DAY EXCRETION
60
50
40
30
20
10
0
DEC.
JAN.
FEB.
MAR. APR.
genital adrenal hyperplasia. The values were low, and little change, if any, was elicited in response to stimulation by ACTH and suppression by 9-alpha- fluorocortisol. In the hypertensive variation, plasma steroid levels, measured as Porter-Silber chromogens, are elevated and respond to both stimulation and sup- pression. This is attributed to compound S, which, unlike 17-hydroxyprogesterone, reacts with the Por- ter-Silber reagent.
Another characteristic difference between virilism due to hyperplasia and that due to carcinoma of the adrenal cortex is the high level of urinary dehydro- epiandrosterone excretion in the latter. This may be detected readily by a simple but apparently nonspecific qualitative test described by Allen et al.1º The test was negative in the case under discussion.
The autonomous behavior of endocrine tumors has been used as a diagnostic feature to differentiate adrenal tumors from hyperplasia.11 However, several exceptions have been recorded. Hardy12 described a twenty-eight-year-old white woman with symptoms of
virilism for eighteen months in whom an adrenocorti- cal carcinoma was found. Elevation of 17-ketosteroid excretion, which increased even further after ACTH stimulation, was noted. After the tumor was removed normal 17-ketosteroid production resulted, but three months later the 17-ketosteroid excretion had in- creased again. In this case, however, there was also a moderate elevation of urinary 17-hydroxycortico- steroids, but no increase in the urinary levels after ACTH stimulation. Gallagher and his associates13 also presented a case in which an adrenocortical car- cinoma was not autonomous but responded to ACTH and cortisone; amphenone markedly suppressed the production of all steroids. We have not administered amphenone to our patient. Lindsay et al.14 reported several cases of Cushing’s syndrome, some associated with hyperplasia and others with adenoma and car- cinoma. All patients with hyperplasia responded to ACTH with an increase in steroid production. In the 1 carcinoma presented there was no response to ACTH, but 1 patient with Cushing’s syndrome asso- ciated with an adrenal adenoma did show a definite response in increasing the production of 17-hydroxy- corticoid to ACTH. In the case reported above, there was also an unequivocal response to both cortisone and ACTH before and after operation. However, the
340
ANT. PITUIT.
DECREASED CORTISOL PRODUCTION YIELDS INCREASED ACTH SECRETION
ADRENAL
“ACETATE” ( INTERMEDIATE STAGES UNDEFINED )
CHOLESTEROL
URINE
PREGNENOLONE
INCREASED ANDROGEN ACTIVITY
MEASURED IN URINE AS INCREASE 17 KETOSTEROID
3 B-DEHYDROGENASE
17-HYDROXYLATING SYSTEM
PROGESTERONE
MEASURED IN URINE AS PREGNANDIOL
17-OH PROGESTERONE
MEASURED IN URINE AS PREGNANTRIOL
2H-HYDROXYLATING SYSTEM
NORMALLY A MINOR SECRETORY PRODUCT WITH BLOCK HERE THIS COMPOUND BECOMES A MAJOR SECRETORY PRODUCT.
COMPOUND S
II-HYDROXYLATING SYSTEM
NORMALLY A MINOR SECRETORY PRODUCT. BLOCK HERE CAUSES COMPOUND S TO BE A MAJOR SECRETION.
CORTISOL
suppression by 9-alpha-fluorohydrocortisone before surgery was incomplete. The elevation of pregnantriol in this case is also of unusual interest and has been unreported previously in an adrenocortical carcinoma. However, several patients described by Venning, Weil and Browne,15 Salmon et al.16 and Held17 exhibited increased pregnanediol excretion. The long duration of symptoms is also of interest. Escamilla and John- son18 reported a case of adrenocortical carcinoma re- moved thirty years after the onset of amenorrhea, hirsutism and baldness in a sixty-three-year-old woman. In this case x-ray studies before surgery did
not reveal the tumor, but the markedly elevated 17- ketosteroid excretion was considered to be incom- patible with adrenocortical hyperplasia. Levels as high as 741 mg. per twenty-four hours were found. Of this amount, 571 mg. was present as alpha 17- ketosteroids, and 170 mg. as beta. Postoperatively the 17-ketosteroids returned to normal levels.
Atrophy of the contralateral adrenal gland was found in 29 per cent of the cases of adrenocortical tumors collected by Rapaport et al.1 Several authors have postulated that prolonged hyperplasia may result in tumor formation. In 1940 Lukens and Palmer19 described a case of virilizing adrenal tumor. Symp- toms began at the age of six, and an exploration at the age of eleven showed no disease in either adrenal gland. At the age of seventeen, perirenal air studies showed a tumor of the right adrenal gland, which was removed. Unfortunately, 17-ketosteroids were not available at that time. Lukens19 postulated that hyper- plastic adrenal tissue, under the influence of trophic hormones, resulted in a benign adenoma. Simpson20 believed that a hyperplastic adrenal gland could de- velop adenomatous changes under the influence of ACTH. He reported a case of acromegaly associated with an adrenocortical carcinoma with virilism. He also cited several cases from the literature, notably those of Lynch,21 who described a six-year-old boy with an adrenal tumor who continued to show elevation of the 17-ketosteroids after surgery, and of Wooley,22 who demonstrated that adrenal tumors develop in certain strains of castrated animals. In 1943 Bratrud and Thompson23 described a woman, masculine since very early childhood, who had an adrenal carcinoma removed at the age of thirty-two. At the time of surgery the contralateral adrenal gland was hyper- trophied. No steroid studies were available. It was postulated, but not proved, that this had begun as hyperplasia and had undergone malignant changes.
The possibility must be considered in this case that prolonged stimulation by ACTH resulted in hyper- plasia of the adrenal gland and that the hyperplastic tissue later became a malignant tumor. This is the most reasonable explanation of the chemical findings and the clinical course presented, even though no direct proof can be offered. An alternative explana- tion would be that this had been a carcinoma from inception, but one that had been exceedingly slow growing. The behavioral traits of this tumor could also be explained by the assumption that the basic process was adrenal hyperplasia that, because of pro- longed stimulation, underwent malignant changes, but that the basic responsiveness of the tumor and the residual functional adrenal tissue remained unchanged.
There is a strong temptation not to treat an occa- sional case in an older woman with the adrenogenital syndrome, in the desire to spare expense and possible discomfort. This is particularly true when the patient has adjusted herself well to her disorder. Although definite conclusions are not warranted on the basis of
a single case, we believe that the possibility of malig- nant transformation warrants treatment of adrenal hyperplasia with suppressive drugs.
SUMMARY
A case of virilization associated with an adreno- cortical carcinoma is reported. Unusual features present were responsiveness to stimulation by ACTH and suppression by cortisonelike substances. The long duration of symptoms, inability to demonstrate a tumor twenty-three years before surgery and the presence of pregnantriol in the urine are described. The possibility that chronic stimulation of the adrenal cortex by ACTH resulted in the ultimate develop- ment of an adrenocortical adenocarcinoma is dis- cussed.
We are indebted to the Central Ohio Heart Association, the Institute of Nutrition and Food Technology and the Comly Coleman Fund of Ohio State University for finan- cial aid.
REFERENCES
1. 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.
2. Bongiovanni, A. M., and Eberlein, W. R. Clinical and metabolic variations in adrenogenital syndrome. Pediatrics 16:628-636, 1955.
3. Reifenstein, E. C. 17-alpha-hydroxyprogesterone and virilism of adrenogenital syndrome associated with congenital adrenocortical hyperplasia - review. J. Clin. Endocrinol. 16: 1262-1275, 1956.
4. Butler, G. C., and Marrian, G. F. Isolation of pregnane-3, 17, 20-triol from urine of women showing adreno-genital syndrome. J. Biol. Chem. 119:565-572, 1937.
5. Bongiovanni, A. M. Detection of pregnandiol and pregnantriol in urine of patients with adrenal hyperplasia: suppression with corti- sone: preliminary report. Bull. Johns Hopkins Hosp. 92:244-251, 1953.
6. Goldzieher, J. W. Lack of androgenicity of 17-hydroxyprogesterone or its 17-caproate ester. J. Clin. Endocrinol. 17:323-325, 1957.
7. Zondek, B., and Finkelstein, M. Quantitative estimation of 3a, 17, 20a-pregnanetriol-11-one in urine as aid in diagnosis of pseudo- hermaphroditic conditions. Acta endocrinol. 17:452-459, 1954.
8. Eberlein, W. R., and Bongiovanni, A. M. Congenital adrenal hy- perplasia with hypertension: unusual steroid pattern in blood and urine. J. Clin. Endocrinol. 15:1531-1534, 1955.
9. Wilkins, L. Diagnosis of adreno-genital syndrome and its treatment with cortisone. J. Pediat. 41:860-874, 1952.
10. Allen, W. M., Hayward, S. J., and Pinto, A. Color test for dehydroisoandrosterone and closely related steroids of use in diag- nosis of adrenocortical tumors. J. Clin. Endocrinol. 10:54-70, 1950.
11. Jailer, J. W., Gold, J. J., and Wallace, E. Z. Evaluation of “cortisone test” as diagnostic aid in differentiating adrenal hyper- plasia from adrenal neoplasia. Am. J. Med. 16:340-345, 1954.
12. Hardy, J. D. Urinary steroids in adrenocortical tumor: excretion of corticoids and 17-ketosteroids on admission, after ACTH, follow- ing resection, after withdrawal of ACTH, and upon recurrence of masculinizing carcinoma. Ann. Surg. 138:765-768, 1953.
13. Gallagher, T. F., Kappas, A., Spencer, H., and Lazlo, D. Influ- ence of invasiveness, hormones, and amphenone on steroids in adrenal carcinoma. Science 124:487-489, 1956.
14. Lindsay, A. E., Migeon, C. L., Nugent, C. A., and Brown, H. Diagnostic value of plasma and urinary 17-hydroxycorticosteroid determinations in Cushing’s syndrome. Am. J. Med. 20: 15-22, 1956.
15. Venning, E. H., Weil, P. G., and Browne, J. S. L. Excretion of pregnandiol glucuronidate in adreno-genital syndrome. J. Biol. Chem. 128: (Proc. Am. Soc. Biol. Chem.) Cvii, 1939.
16. Salmon, U. J., Geist, S. H., and Salmon, A. A. Excretion of pregnandiol in women with virilism. Proc. Soc. Exper. Biol. & Med. 47:279, 1941.
17. Held, E. Adrenogenitales Syndrom bei Karzinom der Nebenniere- ninde. Acta endocrinol. 17:128-135, 1954.
18. Escamilla, R. F., and Johnson, S. G. Successful surgical removal of adrenal cortical adenoma causing virilism for 30 years. Postgrad. Med. 11:272-277, 1952.
19. Lukens, F. D. W., and Palmer, H. D. Adrenal cortical virilism. Endocrinology 26:941-945, 1940.
20. Simpson, S. L. Pituitary-adrenal hyperfunction. Proc. Roy. Soc. Med. 46:39-44, 1953.
21. Lynch, J. Functional tumor of adrenal cortex in male child. J.A.M.A. 144:921-923, 1950.
22. Wooley, G. W. Experimental endocrine tumors with special refer- ence to adrenal cortex. Recent Progr. in Hormone Res. 5:383- 405, 1950.
23. Bratrud, T. E., and Thompson, W. H. Congenital hyperplasia of adrenals. Staff Meet., Bull. Hosp. Univ. Minn. 25: October 8, 1943.