related.6 The serum sodium concentration in the range of 125 mEq/liter was maintained in our patient while she was on a course of 600 mg/day of carbamazepine alone. When on a course of 400 mg daily of carbamazepine, her serum sodium level increased to 130 to 133 mEq/liter. The value became normal following discontinuance of the drug. The percent of water retained during standard oral water loading was similarly demonstrated to be related to drug dosage.
Our patient had done well for several years when taking both carbamazepine and phenytoin. On admittance to the hospital, the patient had profound hyponatremia following discontinuance of the phenytoin and after increasing her daily dosage of carbamazepine. Observations made during hospitalization suggested that phenytoin could prevent hyponatremia since the patient became hyponatremic on carbamazepine alone, but a normal serum sodium level was maintained when the patient was also receiving phenytoin. Further, the hyponatremia was seen to recur in a stepwise fashion as the dose of phenytoin was reduced. These findings are consistent with prior data that have shown phenytoin to be sometimes effective in the treatment of hyponatremia secondary to inappropriate antidiuretic hormone secretion of other causes.10
The change in serum sodium concentration was noted to be prompt on alteration of carbamazepine dosage. Mein- ders et al demonstrated that the antidiuretic effect of carbamazepine disappeared after 48 hours,ª and Uhlrich et al showed that the maximal antidiuretic response to this drug in rats occurs two hours after its administration.15 The serum sodium concentration in our patient in response to decreasing doses of carbamazepine was promptly raised, and excretion of standard oral water load was normal after the patient was off therapy for only 24 hours. Following therapy with both drugs, the decrease in serum sodium concentration also occurred within a few days after removal of the suppressive effect of phenytoin, indicating that this effect of the latter drug is also quickly dissi- pated.
Except for the case described by Rado, patients on carbamazepine have not been shown to develop notable hyponatremia. Rado’s patient developed the SIADH while receiving doses of carbamazepine in excess of the 200 to 1,200 mg daily, usually used clinically. The patient reported herein is the first to develop this syndrome on standard doses of carbamazepine. The patient’s low body weight (37.5 kg) may have been a factor in her sensitivity to the drug. It is proper that body weight be considered in arriving at future dose schedules when using this drug.
References
1. Graham JG, Zilkha KJ: Treatment of trigeminal neuralgia with carbamazepine. Br Med J 1:210-211, 1966.
2. Crill WF: Carbamazepine. Ann Intern Med 79:844-847, 1973.
3. Meinders AE, Cejka V, Robertson GL: The antidiuretic action of carbamazepine in man. Clin Sci Mol Med 47:289-299, 1974.
4. Kimura T, Matsui K, Sato T, et al: Mechanism of carbamazepine (Tegretol)-induced antidiuresis: Evidence for release of antidiuretic hormone and impaired excretion of a water load. J Clin Endocrinol Metab 38:356-362, 1974.
5. Wales JK: Treatment of diabetes insipidus with carbamazepine. Lancet 2:948-951, 1975.
6. Rado JP: Water intoxication during carbamazepine treatment. Br Med / 3:479, 1973.
7. Frahm H, Smejkal E: Nachweis von ADH aktivitaten im serum bei hypophysenoperierten patienten mit polyurie und polydipsie und kranken mit diabetes insipidus unter dem einfluss eines antidiuretisch wirksamen psychotropen antiepileptikums (5-carbamyl-5H-dibenzo-(b, f) Azepin- Tegretol). Verh Dtsch Ges Inn Med 75:777-779, 1969.
8. Lee WY, Grumer H, Bronsky D, et al: Acute water loading as a diagnostic test for the inappropriate ADH syndrome. J Lab Clin Med 58:937, 1961.
9. Fichman MP, Kleeman CR, Bethune JE: Inhibition of antidiuretic hormone secretion by diphenylhydantoin. Arch Neurol 22:45-53, 1970.
10. Fichman MP, Bethune JE: The role of adrenocorticoids in the inappropriate antidiuretic hormone syndrome. Ann Intern Med 68:806-820, 1968.
11. Michelis MF, DeRubertis F, Beck NP, et al: Standard oral water load to determine the site of action of diuretics in man. Clin Pharmacol Ther 11:821-828, 1970.
12. Schwartz WB, Bennett W, Curelop S, et al: A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 23:529-542, 1957.
13. Bartter FC, Schwartz WB: The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 42:790-806, 1967.
14. Moses AM, Miller M: Drug induced dilutional hyponatremia. N Engl J Med 291:1234-1239, 1974.
15. Uhlrich E, Loeschke K, Eigler J: Zur antidiuretischen wirkung von carbamazepin bei diabetes insipidus. Klin Wochenschr 50:1127-1133, 1972.
Feminizing Adrenocortical Carcinoma With Cushing’s Syndrome and Pseudohyperparathyroidism
Diosdado N. deAsis, Jr, MD, Naguib A. Samaan, MD, PhD
. A patient with adrenocortical carcinoma had three major endocrine abnormalities attributable directly to the tumor: hyper- cortisolism (Cushing’s syndrome), hyperestrogenism (feminiza- tion), and hypercalcemia (pseudohyperparathyroidism). There were higher levels of immunoreactive parathyroid hormone in venous effluent from the tumor or its abdominal metastases compared to that found in the veins draining the parathyroid glands. This, together with the presence of normal parathyroid glands on autopsy, established the diagnosis of pseudohyper- parathyroidism as the cause of hypercalcemia in this patient. (Arch Intern Med 138:301-303, 1978)
C Cushing’s syndrome and virilization are the most common clinical manifestations of carcinoma of the adrenal cortex. Recently, we studied a patient who had clinical and biochemical evidence of Cushing’s syndrome, feminization, and pseudohyperparathyroidism. To our knowledge, such an association has not previously been reported in patients with adrenocortical carcinoma.
REPORT OF A CASE
In May 1975, a 31-year-old man was seen with low back pain radiating to the right lower extremity. A myelogram showed an extradural defect in the L-1 and L-2 region. On Nov 10, 1975, an adrenal mass was diagnosed and a right adrenocortical tumor was removed. He was referred to M. D. Anderson Hospital on Nov 22, 1975.
The patient weighed 79.4 kg; his height was 173.1 cm. He had a blood pressure of 140/100 mm Hg, moon facies, buffalo hump, violaceous pink striae over both axillae and groins, bilateral gynecomastia without galactorrhea, abdominal scar from a
Accepted for publication June 8, 1977.
From the Section of Endocrinology, Department of Medicine, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston.
Reprint requests to Section of Endocrinology, Department of Medicine, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Ave, Houston, TX 77030 (Dr Samaan).
| Urinary 17-KS, mg/Day | Urinary 17-OHCS, mg/Day | Plasma Cortisol, ug/100 ml | Testosterone, ng/100 ml | Androstenedione, ng/100 ml | Estrone, pg/ml | Estradiol, pg/ml | |
|---|---|---|---|---|---|---|---|
| Admission | 31.3 | 12.6 | AM, 34.6 PM, 33.8 | 30.4 | 187.9 | 494 | 133 |
| Dexamethasone, 0.5 mg q6h x 8 doses | 31.3 | 12.8 | 38.6 | 58.4 | 206.9 | 495 | 132 |
| Dexamethasone, 2.0 mg q6h x 8 doses | 25.2 | 22.7 | 27.6 | ||||
| Mitotane, 3 gm/day + metyrapone, 750 mg po q6h (12/11/15-1/15/76) | 19.2 | 16.4 | 43.0 | 34.0 | 288.0 | 4,778 | 575 |
| Mitotane, 3 gm/day + metyrapone, 750 mg po q6h, + aminoglutethimide, 1 gm/day + dexametha- sone, 0.5 mg po q6h (1/15/76-2/6/76) | 27.5 | 179.0 | 1,207.0 | 5,889 | 369 | ||
| Mitotane, 2 gm/day + metyrapone, 750 mg po q6h, + dexamethasone, 0.5 mg po q6h (2/7/76-2/24/76) | 31.0 | 25.0 | 88.0 | 148.0 | 1,694.0 | 21,988 | 613 |
| Normals (male) | 9-22 | 3-10 | AM, 8-19 PM, 4-11 | 280-1,200 | 75-205 | 29-75 | 8-35 |
*KS, ketosteroids; OHCS, hydroxycorticosteroids, q6h, every six hours; po, orally.
previous right adrenalectomy, small soft testicles, and decreased sensation to pain over the anterior and lateral aspect of the right thigh.
Radiological studies disclosed metastases to the lungs, T-10, and L-2 vertebrae. Liver scan was normal. Decompression laminec- tomy of L-2 and L-3 was performed on Dec 1, 1975 and followed by radiotherapy to the lumbar region.
After an endocrine evaluation that confirmed hypercortisolism and hyperestrogenism (Table 1), which were attributed to his tumor, the patient was discharged on a regimen of mitotane, 3 gm/day, metyrapone, 750 mg four times a day, and aminoglute- thimide, 250 mg four times a day. On Feb 2, 1976, the patient complained of increasing lethargy, nausea, emesis, anorexia, and generalized weakness. A chemical survey showed a serum calcium level of more than 15 mg/100 ml. Serum total protein level was 7.1 gm/100 ml; serum albumin, 5 gm/100 ml; and serum inorganic phosphate, 4.2 mg/100 ml. Roentgenographic studies showed progression of metastases in the lungs, skull, and spine. A month later, the patient died of pulmonary edema.
Postmortem examination confirmed gynecomastia consisting of ductal proliferation with intraglandular papillary formation. The testicles showed prominent hyalinization of the tubular basement membranes, focal increase of Leydig cells, and diminished sperma- togenesis. The lungs showed hyaline membrane formation and diffuse intraalveolar hemorrhage that resembled “shock lung.” The kidneys had calcinosis. Metastatic adrenocortical carcinoma was found in the liver, lungs, both retroperitoneal areas, especially around the left adrenal gland which was small, and in various bones including the thoracic and lumbar vertebrae, skull, and ribs. All four parathyroid glands were normal in size and histologic features.
RESULTS
Before therapy, the 24-hour levels of urinary 17-hydroxy- corticosteroids (17-OHCS) and 17-ketosteroids (17-KS) were elevated. Peripheral plasma testosterone level was low, the plasma androstenedione level was normal, but plasma estrone and estradiol levels were elevated (Table 1). Serum immunoreactive luteinizing hormone (LH) was subnormal at basal and after intravenous injection of 100 ug/sq m of luteinizing hormone-releasing hormone (LH- RH). The basal serum LH concentration was 0.8 mU/ml with a peak of 5 mU/ml (second international standard for
human chorionic gonadotrophin), compared with 3.3 ± 1.6 (SD) mU/ml and a peak of 85 ± 30 (SD) mU/ml in six normal male subjects of the same age range (25 to 40 years) (P < . 001). Serum follicle-stimulating hormone (FSH) level was subnormal both at basal and after LH-RH stimulation. The basal serum FSH level was 0.8 mU/ml with a peak of 3.2 mU/ml, compared with 4.5 + 0.9 (SD) mU/ml at basal and a peak of 14.2 ± 5.7 (SD) mU/ml in normal subjects (P < . 001). Urinary aldosterone concentration was normal at 15.9 ng/24 hr (normal, 3 to 19 ng/24 hr). The serum triiodothyronine resin uptake was 28.3% (normal, 22% to 33%), and serum thyroxine iodine level was 4.6 µg/100 ml (normal, 3.6 to 6.6 µg/100 ml). There was no suppression of either urinary 17-OHCS or plasma cortisol levels by admin- istration of either low (2 mg/day) or high (8 mg/day) doses of dexamethasone. The urinary 17-KS level decreased and plasma estrogen concentration increased while the patient was receiving mitotane and metyrapone. When aminoglu- tethimide, 1 gm/day, and dexamethasone, 0.5 mg every six hours, were added, the plasma estrogen levels remained high, and plasma testosterone level increased, but remained below normal. The rise in plasma testosterone level possibly reflected some degree of increased conver- sion from androstenedione, which increased considerably. Prior to the patient’s death, his urinary and plasma steroids, plasma androstenedione, and plasma estrogen values remained elevated, while the plasma testosterone level was still low. Oral glucose tolerance testing yielded a diabetic curve. The patient was mildly hypokalemic.
The immunoreactive parathyroid hormone (iPTH) results obtained at catheterization from the neck veins were lower than those from the venous effluent of abdom- inal metastases (Table 2). Although samples from these two regions were taken on different days, iPTH was measured in the same assay to avoid interassay variation. The intraassay variation in our laboratory is < 3%, while the interassay variation is < 10%. In spite of sampling on different days, the iPTH levels in the inferior vena cava at the iliac veins remained the same. These results indicated that the adrenal tumor and the abdominal metastases were
| IPTH, ng/ml | |
|---|---|
| Neck vein catheterization (2/26/76) | 1.0 |
| Right innominate | |
| Superior vena cava | 0.78 |
| Right superior thyroid | 0.73 |
| Right middle thyroid | 1.0 |
| Low right jugular | 0.85 |
| High right jugular | 0.87 |
| Right middle jugular | 0.95 |
| Middle left jugular | 0.78 |
| High left jugular | 0.95 |
| Left inferior thyroid | 0.75 |
| Right inferior thyroid | 0.80 |
| Left innominate | 0.95 |
| Inferior vena cava at iliac veins | 1.2 |
| Retrograde transfemoral venous catheterization (3/2/76)} | 1.3 |
| Inferior vena cava at iliac veins | |
| Inferior vena cava at clips (right adrenalectomy) | 4.9 |
| Left renal vein | 4.6 |
| Distal-left adrenal vein | 5.2 |
| Right renal vein | 4.2 |
| Hepatic vein | 4.9 |
| Proximal right renal vein | 2.1 |
| Normal (N = 10) 0.5 ± 0.2 |
*Serum calcium level, 12.9 mg/100 ml.
+Serum calcium level, 12.3 mg/100 ml.
the sites of origin of ectopic production of iPTH. The patient’s serum iPTH level had a parallel dilution curve in reference to the standard using an antibody against the aminoterminal region of the parathyroid hormone mole- cule.1
COMMENT
Cushing’s syndrome and virilization are frequent accompaniments of carcinoma of the adrenal cortex, but feminization is rare.2.3 Our patient had typical clinical and biochemical features of Cushing’s syndrome together with feminization attributable to high levels of circulating estrogens.
Selective activation of the synthetic pathways that lead to cortisol and androstenedione synthesis with a partial defect of 17-8-hydroxylase activity would probably explain the joint occurrence of feminization and Cushing’s syndrome in this patient. The aromatization of androsten- edione to estrone and its hydroxylation to estradiol appears to have been enhanced by a specific induction of this normally inactive pathway. Elevated estrogen levels were probably responsible for impaired secretion of both LH and FSH, causing testicular atrophy and low plasma testoste- rone levels. In addition, the inhibition of LH secretion could be caused by hypercortisolism.+
The administration of metyrapone to treat the patient’s hypercortisolism resulted in an increase of plasma estrogens and androstenedione. Metyrapone produces an incomplete block of 11-B-hydroxylation,” thus diverting steroid synthesis to increased androstenedione production and its aromatization to estrogens.6
Solomon et al’ reported a case of feminizing adrenocor- tical carcinoma and cited three other cases in which aldosterone levels appeared to account for the hyperten- sion. Our patient had normal urinary aldosterone levels, and his hypertension may be attributable to the presence of excessive amounts of cortisol and other mineralocorti- coids that were not measured.
Of special interest was the hypercalcemia noted while the patient received a combination of metyrapone, mito- tane, and aminoglutethimide. There are no reports of hypercalcemia being caused directly by these drugs. The possibility of drug-induced Addison’s disease to account for the hypercalcemia is untenable since the patient still had elevated plasma cortisol levels on this regimen. The differ- ential diagnosis between the ectopic production of iPTH by the adrenal tumor or its metastases (pseudohyperparathy- roidism) and coexisting primary hyperparathyroidism1 appears to be resolved in favor of pseudohyperparathy- roidism by the presence of high levels of iPTH in veins draining the tumor and its abdominal metastases relative to neck vein levels of iPTH. The finding of normal parathyroid glands at autopsy further supports this conclu- sion. Only one other report of adrenocortical carcinoma associated with hypercalcemia and high levels of extract- able iPTH from the tumor is known to us.& Unfortunately, tumor tissue was not available for extraction in this patient.
We consider this unique patient to have had an adreno- cortical carcinoma in which the tumor was responsible for the simultaneous occurrence of three major endocrine abnormalities: hypercortisolism (Cushing’s syndrome), hyperestrogenism (feminization), and hypercalcemia (pseudohyperparathyroidism).
This investigation was supported in part by grants CA 05831-16 and CA- 16672-02 from the National Cancer Institute and grant ACS PDT-41E from the American Cancer Society.
The National Pituitary Agency supplied the LH antibody. The British Medical Research Council supplied the second international standard for human chorionic gonadotrophin. The Ayerst Company, New York, provided the LH-RH. Socorro Castillo, Carolyn Marshall, and Maria Elsa Pope gave technical assistance.
Nonproprietary Name and Trademark of Drug
Aminoglutethimide-Cytadren.
References
1. Samaan NA, Hickey RC, Sethi R, et al: Hypercalcemia in patients with known malignant disease. Surgery 80:382-389, 1976.
2. Gabrilove JL, Sharma DC, Wotiz DD, et al: Feminizing adrenocortical tumors in the male. Medicine 44:37-79, 1965.
3. Gabrilove JL, Nicolis GL, Hausknecht RU, et al: Feminizing adrenocor- tical carcinoma in man. Cancer 25:153-160, 1970.
4. Boccuzzi G, Angeli A, Bisbocci D, et al: Effect of synthetic luteinizing hormone releasing hormone (LH-RH) on the release of gonadotropins in Cushing’s disease. J Clin Endocrinol Metab 40:892-895, 1975.
5. Kumagai LF, West CD: Steroid production in feminizing adrenocor- tical carcinoma and results of therapy with DDD. Clin Res 8:110-115, 1960.
6. McKerns KW: Steroidogenesis and metabolism in the adrenal cortex, in Steroids, Hormones and Metabolism. New York, Appleton-Century-Croft, 1969, chap 2.
7. Solomon SS, Swersia SP, Paulsen CA, et al: Feminizing adrenocortical carcinoma with hypertension. J Clin Endocrinol Metab 28:608-612, 1968.
8. Sherwood L, O’Riordan J, Aurbach G, et al: Production of parathyroid hormone by nonparathyroid tumors. J Clin Endocrinol Metab 27:140-146, 1967.