Endocrine Clinic
Such great strides have been made in the field of endocrinology and metabolism in recent years that the average physician has found it difficult to keep abreast of them. In a series of Endocrine Clinics an attempt will be made to show how new methods can be of value in demonstrating aberrations in endocrine function and how these aberrations may be corrected by judicious therapy.
Cushing’s Syndrome Secondary to Adrenocortical Carcinoma
R. GLENN GREENE, M.D .. and GRANT W. LIDDLE. M.D.,t Nashville, Tenn.
DURING THE PAST DECADE a number of develop- ments have combined to increase the case with which Cushing’s syndrome can be cor- rectly recognized and treated. The wide use of steroids and corticotropin as therapeutic agent> has served to make physicians in gen- eral more keenly aware of adrenocortical dis- orders. The development of technics for the determination of adrenal hormones in bio- logic fluids has made it possible to define deviations from normal with considerable pre- cision. And, finally, the availability of syn- thetic corticoids has made it possible to cure hyperadrenocorticism without incurring the formerly prohibitive risk of adrenal insuf- ficiency.
In his classic description of the disease which bears his name, Cushing1 emphasized the features of central adiposity, osteoporosis, amenorrhea, hypertrichosis, purplish striae, hypertension, erythremia, and weakness. An- derson and her associates” were among the first to present evidence showing that the probable common denominator of all cases of Cushing’s syndrome was hyperactivity of the adrenal cortex. Albrightª drew a clear distinction between the adrenal disorders characterized by virilization and “pure” Cush- ing’s syndrome, the cardinal manifestations of which were properly ascribed to the chronic oversecretion of the adrenocortical “S” (sugar) hormone. It is now known that the “S” hor- mone of Albright is hydrocortisone. The excess
hydrocortisone in Cushing’s syndrome may be secreted by diffusely overactive adrenal glands (many of which are morphologically recogniz- able as hyperplastic) or, less commonly, by adrenocortical tumors, benign or malignant.
The following case of Cushing’s syndrome associated with adrenocortical carcinoma is described for the purpose of illustrating methods currently available for the diagnosis and treatment of hyperadrenocorticism, em- phasizing those aspects which are peculiar to adrenocortical carcinoma.
Case Presentation
The patient.” a 49 year old white woman, entered the hospital in October, 1956, complaining of a two year history of weight gain, deepening of the voice. acne, high blood pressure. “nervousness,” and a suf- ficient increase in facial hair to require frequent shaving. Her previously regular menstrual periods had ceased in January. 1955, and frequent “hot flashes” were noted thereafter. Nine months prior to admis- sion she had undergone radical mastectomy for adeno- carcinoma of the left breast. No metastases have ap- peared to date, 22 months later.
Physical examination (Fig. 1) revealed the patient to have a full and ruddy face. The trunk was obese, but the extremities were slender. Acneform lesions were noted on the face and shoulders. Coarse black hair was found over the upper lip, chin, legs, and forearms. No striae were present. The voice was hoarse. Tinea versicolor was noted on the chest and back. Scalp hair was wavy. There was definite temporal recession of the hair line. Pubic hair was of masculine distribution. Blood pressure was 190/110. No abdomi- nal or pelvic masses were palpable. The clitoris was approximately 3 times enlarged.
Laboratory data included the following: Hgb. 17
tFrom the Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
This study was made possible through a grant-in-aid from The John A. Hartford Foundation.
*Referred to Vanderbilt University Hospital by Dr. James R. Dade of Hopkinsville, Ky.
A
F
Photographs of patient taken (A) immediateh betore, and ( B) $ months following removal of adrenocortical tumor.
Gm. "" ;: hematocrit 5025 ;: white blood cells 6,900 per cu. min .: a normal differential blood count: blood eosinophils 34 per cu. mm .: serum sodium 130 mEq./1: potassium 4.3 mEq./1: CO., 25 mEq./1: chloride 93 mEq./1: calcium 8.8 mg./100 ml .: inorganic phosphorus 2.7 mg./100 ml .: alkaline phosphatase 2.7 Bodansky units. Oral glucose tolerance test: fasting blood sugar 101. 1 hour 224. 215 hours 116 mg. per cent. Electro- cardiogram was normal except for slight depression of S-T segments and T waves in all leads. Intravenous Regitine 5 mg. failed to cause a significant fall in blood pressure, and intravenous histamine 0.025 mg. failed to induce a significant rise in blood pressure. Urinalysis was negative.
Steroid excretion data are depicted in figure 2. Phase I. The elevation of 17-hydroxycorticoids and 17-ketosteroids under “basal” conditions, the failure of these steroids to rise during treatment with cortico- tropin (ACTH) and their failure to fall during treat- ment with A1.9a-fluoro-hydrocortisone are especially significant. .
X-ray studies demonstrated moderate demineraliza- tion of the spine. pelvis, and ribs, and a fracture of the left 7th rib. Skull films and a gastrointestinal series were normal. Intravenous urography indicated displacement of the right kidney downward and laterally.
Operative management: With the patient under general anesthesia, the right adrenal area was exposed through a right thoracico-abdominal incision. A well- encapsulated adrenal tumor weighing 384 Gm. was
removed. Regional exploration revealed no evidence of metastases. Microscopic examination of the tumor indicated it to be adrenocortical carcinoma (Fig. 3).
Medical management: Hydrocortisone sodium succi.
nate (Solu-Cortef) 100 ing. was injected intramuscularly
2 hours before the patient was taken to the operating
room. A peripheral vein was cannulated in order to
avoid difficulty in providing intravenous therapy. .
precipitous fall in blood pressure. when the patient
was placed on the operating table. prompted the
administration of norepinephrine diluted + ing. per
liter which was given by slow intravenous infusion
whenever required to prevent the systolic blood pres-
sure from falling below 100 mm. Hg. Hydrocortisone
sodium succinate 200 mg. was given as a continuous
intravenous infusion during the immediate 24 hour
period following the operation. Fluids infused during
this period were 1.000 cc. of 5% dextrose in water
and 1,000 cc. of 50% dextrose in normal saline. There.
after. an ad libitum diet was resumed. On the first
postoperative day hydrocortisone sodium succinate 50
mg. was injected intramuscularly every 6 hours. On
the second postoperative day hydrocortisone 20 mg.
was given orally every 6 hours. Over the ensuing week
the dose of oral hydrocortisone was gradually de-
creased to 10 mg. twice daily. Treatment way con.
tinued at this level until May, 1957. when a course
of ACTH therapy was given. Since that time no sub-
stitution therapy has been required except for occa-
sional injections of ACTH gel to overcome the symp-
tom of “weakness.” No DOCA or other salt-retaining
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Daily urinary 17-hydrowwcorticoids and 17-Actosteroid. Arrows represent 8 hour intravenous infusions of ACTH. Phew I: Note the high “basal” levels of 17-hydroxycorticoids and 17-Letosteroids and the lack of response to an ACTH infusion or to AT-Ja-fluoro.hydrocortisone (AFF), Phase II: Following removal of the adrenal tumor the steroid levels were low and te- spouse to ACTH was negligible. Phase III: Following a course of treatment with ACTH gel a standard intravenous ACTH text clicited a normal response.
steroid was given at any time.
Postoperative studies of steroid excretion are de- picted in figure 2. Phase 11. During the immediate postoperative period the previously excessive urinary levels of 17-hydroxycorticoids and 17-ketosteroids were negligible, both under basal conditions and during stimulation with ACTH.
Aldosterone secretion by the left adrenal gland was apparently adequate inasmuch as the patient required neither salt nor salt-retaining steroids postoperatively. Following a deliberate course of treatment designed to deplete the patient’s sodium “reserves” dlow sodium diet and injection of a mercurial diuretic), the patient exhibited a normal rise in urinary aklosterone and a normal decrease in urinary sodium.
Pituitary-adrenal response to stress: In May. 1957.
Photomicrograph of a section of the adrenal cortical tumor. Magnification 950 X.
the patient was readmitted to the hospital for surgical exploration of a mass in the right breast and for a course of treatment with ACTH in order to restore her left adrenal gland to a normal state of responsive- ness. Hydrocortisone substitution therapy was with- drawn and a standard test of adrenal responsiveness was done (Fig. 2. Phase 111). Although adrenal re- sponsiveness to ACTH was still subnormal it had, nevertheless, increased appreciably during the post- operative interval of 7 months despite the fact that the patient had been receiving hydrocortisone in doses of 10 mg. twice daily. The patient was then given a 5 day course of corticotropin gel 40 units intra- muscularly every 12 hours. Repetition of the standard ACTH test at this time revealed adrenal responsive- ness to be within normal range. One day following the last ACTH test a simple mastectomy was per- formed under general anesthesia. Neither ACTH nor steroids were administered for 16 hours before or dur- ing the operation. The procedure was tolerated well until the patient was removed to the recovery room. when her systolic blood pressure fell to 80 min. Hg. Her circulating cosinophils at this time were found to be 118 per cu. mm., and the concentration of plasma 17-hydroxycorticoids was 31 ing. per cent. This latter value is to be contrasted with a plasma 17-hydroxy- corticoid value of 45 mg. ”; obtained on the previous day during the third hour of an intravenous infusion of ACTH and indicates that under conditions of surgical stress the patient’s pituitary failed to secrete enough ACTH to induce maximal adrenocortical ac- tivity.
Clinical course: Following removal of the adrenal tumor the patient experienced considerable loss of vigor. This has gradually improved over the subse- quent year. The facial and truncal obesity have dis- appeared as have the acne and hirsutism, Scalp hair has increased and has lost much of its tendency to curl. Serial x-rays of the spine. pelvis, and ribs have
revealed no appreciable change in the degree of osteo- porosis. The previously excessive blood pressure has consistently been found to be approximately 120 80. The glucose tolerance curve remains slightly abnormal although fasting blood sugar is now normal at $0 mg. per cent. The S.T and T wave abnormalities prevent in the preoperative electrocardiogram have disappeared. In July, 1937. the patient testmed regular menstruation after having had amenorrhea for 216 years. Metastases from the adrenal tumor have not appeared.
Discussion
The most important steroid of the human adrenal cortex in facilitating the adaptation to various physiologic “stresses” is hydrocorti- sone. Hydrocortisone is secreted by the nor- mal adrenal cortex only in response to stimu- lation by ACTH from the pituitary. Hydro- cortisone in turn tends to suppress the secre- tion of ACTH. so that both hydrocortisone and ACTH levels normally remain within relatively narrow limits. Hydrocortisone and its major metabolites are identifiable in blood and urine by the chromogenic reaction of Porter and Silber.+
A number of other steroids are also secreted by the adrenal cortex in response to ACTH. These steroids have little known importance physiologically, and they have little or no ACTH-suppressing activity. Some of them are weakly androgenic. Some are chemically iden- tifiable as 17-ketosteroids. Teleologically, it is convenient to regard them as by-products of hydrocortisone secretion.
At least one adrenal steroid, aldosterone. is regulated by a mechanism other than the pituitary.” The secretion of aldosterone is not dependent upon ACTH, and aldosterone has no significant ACTHsuppressing action. It is this steroid which is of chief importance in promoting sodium conservation and potassium excretion by the kidneys.
Cushing’s syndrome may be regarded as the clinical consequence of chronic oversecretion of hydrocortisone. The chemical hallmark of Cushing’s syndrome is that of excessive 17- hydroxycorticoids in plasma or urine. There may or may not be excessive levels of other steroids such as 17-ketosteroids and aldos- terone. Among different patients there are im- pressive variations in the clinical and labora- tory manifestations which have become asso- ciated with the syndrome. It is, therefore, im- possible to exclude the diagnosis of hyper- adrenocorticism by citing the absence of cer-
tain features of the syndrome. Patients in whom the diagnosis of Cushing’s syndrome is suspected on clinical grounds are entitled to studies of plasma or urinary 17-hydroxycorti- coids in an effort to establish or exclude a “chemical diagnosis” of hyperadrenocorticism.
The method of Silber and Porter gives urinary 17-hydroxycorticoid values of 4 to 10 mg. per day in normal adults. “Basal” values in excess of 12 mg. per day are characteristic of Cushing’s syndrome and are almost never encountered in normal individuals. The pa- tient described in this report exhibited levels of 15 to 28 mg. per day prior to treatment.
If the chemical diagnosis of hyperadreno- corticism is established through the demon- stration of high 17-hydroxycorticoid levels, further information regarding the functional state of the adrenals can be obtained by per- forming a “standard ACTH stimulation test.” This test is carried out by the intravenous infusion of corticotropin, 50 units. over ex- actly 8 hours. Most normal adults excrete from 20 to 40 mg. of 17-hydroxycorticoids dur- ing the 24 hour period corresponding to this infusion. Patients with Cushing’s syndrome due to bilateral adrenocortical hyperplasia, and most of those with a benign adrenal adenoma producing Cushing’s syndrome re- spond to this test with a marked increase in steroid excretion, generally excreting in ex- cess of 50 mg. of 17-hydroxycorticoids on the day of the test. By way of contrast, patients with Cushing’s syndrome due to adrenocorti- cal carcinoma fait to respond with any sub- stantial increase over their “basal” steroid output. (A single well-documented exception to this rule has been reported.)” Our patient was suspected preoperatively of having adrenal carcinoma on the basis of her failure to re- spond to ACTH.
Normally the pituitary-adrenal mechanism is easily suppressed by the administration of hydrocortisone-like steroids. For example. 41-9a-fluoro-hydrocortisone in doses of 0.5 mg. every 6 hours regularly causes a fall in 17- hydroxycorticoid excretion to about 1 mg. daily in normal individuals. In patients with Cushing’s syndrome, however, the secretion of adrenal steroids is generally not suppressible by this treatment.
Since the adrenocortical carcinoma was pro- ducing such large amounts of ACTH-sup- pressing steroids, this patient’s nontumorous
Normal pituitary-adrenal relationship. ACTH from the pituitary stimulates growth of adrenal cortex and induces secretion of hydrocortisone. Hydrocortisone suppresses further secretion of ACTH.
Exogenous hydrocortisone suppresses secretion of ACTH by pituitary, permitting atrophy of adrenal cortex and cessation of hydrocortisone secretion.
Hydrocortisone from adrenal carcinoma acts like exogenous hydrocortisone. The non- tumorous adrenocortical tissue undergoes atrophy and becomes unresponsive to ACTH. The ancinoma is neither dependent upon ACTH nor responsive to ACTH.
Removal of adrenal carcinoma permits pituitary to resume secretion of ACTH. The atrophic adrenocortical tissue requires time to regain its responsiveness to ACTH.
Eventually the adrenal atrophy is reversed and a normal pituitaryadrenal relationship is re-established.
adrenal tissue was atrophic and unresponsive to ACTH. The relationships between pituitary and adrenal cortex at various stages of the patient’s illness are depicted diagrammatically in figure 4.
The fact that the nontumorous adrenocorti- cal tissue was atrophic required that hydro- cortisone substitution therapy be employed following removal of the tumor. On the other hand, the survival of this atrophic adrenal tissue made the long-range management of this patient simpler than that of the totally adrenalectomized individual in two important regards. First, the atrophic adrenocortical tis- sue retained its capacity to secrete aldosterone; therefore, neither salt nor sodium-retaining steroids were required. Second, the atrophic adrenocortical tissue under the influence of endogenous and exogenous ACTH ultimately regained its hydrocortisone secreting capacity. Barring the eventuality of metastases, there- fore, the ultimate prognosis seems very fa- vorable.
Summary
A case of Cushing’s syndrome associated with a malignant adrenocortical tumor has been described. The outstanding diagnostic features were those of elevated 17-hydroxycor- ticoids and 17-ketosteroids which failed to in- crease further during administration of ACTH and which failed to decrease during adminis- tration of 41-9a-fluoro-hydrocortisone. Clini- cal and biochemical recovery ensued following surgical removal of the tumor.
References
1. Cushing. H .: The Basophil Adenomas of the Pituitary Body and Their Clinical Manifestations ( Pituitary Ba- wophilism), Bull. Johns Hopkins Hosp. 50:137. 1932.
2. Anderwon, E., Haymaker, W., and Joseph. M .: Hormone and Electrolyte Studies of Patients with Hyperadrenocor- tical Syndrome (Cushing’s Syndrome), Endocrinology 23:398. 1938.
3. Albright, F .: Cushing’s Syndrome. The Harvey Lectures 38:123, 1942-3.
1. Silber. R. H., and Porter, C. C .: The Determination of 17.21-dihydroxv.20.ketosteroids in Urine and Plasma. J. Biol. Chem. 210:023. 1954.
5. 1.iddle. G. W., Duncan, I. E., Jr., and Bartter. F. C .: Dual Mechanism Regulating Adrenocortical Function in Man. Am. J. Med. 31:380. 1956.
6. Soffer, L. J., Geller. J., and Gabrilove. J. 1 ..: Reymse of Plasma 15-OH-CS to gel-ACTH in Tumorous and Non-tumorous Cushing’s Syndrome, J. Clin. Endocrinol. 17:878. 1937.