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Endocrine studies in a male patient with choriocarcinoma and gynecomastia
Endocrine Studies in a Male Patient with Choriocarcinoma and Gynecomastia
RANDALL W. WHITCOMB, M.D.* R. NEIL SCHIMKE, M.D. JOSEPH L. KYNER, M.D. BARBARA P. LUKERT, M.D. DONALD C. JOHNSON, Ph.D. Kansas City, Kansas
Sex hormone profiles were studied in serum and tumor extracts of a man with pulmonary choriocarcinoma and gynecomastia. Although levels of serum estrogens were elevated as expected, serum androgen levels were uncharacteristically quite high. Tumor extract contained increased quantities of both androgens and estrogens when compared with surrounding normal lung tissue, but lacked the enzymes necessary for androgen biosynthesis while retaining aromatase activity. It is concluded that unlike the usual male patient with choriocarcinoma, the tumor-derived beta-human chorionic gonadotropin stimulated testicular androgen production. These androgens were in turn concentrated by the tumor and converted in part to estrogens. Furthermore, gynecoma&a can occur even in the face of high serum androgen concentrations provided total estrogen levels are also disproportionately elevated. Male patients with choriocarcinoma often first present with gynecomastia. The gynecomastia is generally considered to be secondary to a decreased androgenjestrogen ratio [ 1,2], but the reason for this alteration in nontesticular tumors is not always clear. In a number of instances, the gynecomastia has been long-standing and the patient was found to have the Klinefelter syndrome, a condition that seems to predispose to extragonadal germ cell tumors [3]. Because of the apparent uncertainties about steroid metabolism in male patients with germ cell tumors, we studied tumor and tumor extracts from a 46,XY patient with choriocarcinoma.
CASEREPORT
From the Division of Endocrinology, Metabolism and Genetics, Department of Internal Medicine and the Department of Physiology, University of Kansas School of Medicine, Kansas City, Kansas. This work was supported in part by the Hinman fund. Requests for reprints should be addressed to Dr. R. Neil Schimke, Department of Medicine, University of Kansas School of Medicine, 39th and Rainbow Boulevard, Kansas City, Kansas 66103. Manuscript submitted May 9, 1985, and accepted July 9, 1985. *Current address: National Institutes of Health, Building 10, Room lON262, Bethesda, Maryland 20892.
A 41-year-old man presented with a two-week history of painful bilateral gynecomastia. He specifically denied having galactorrhea. There was no significant past medical history and he was taking no medications. On physical examination, 3 to 4 cm of glandular breast tissue could be palpated bilaterally. Results of the remainder of the physical examination were unremarkable including careful testicular palpation. Chest radiography showed a 5 cm mass in the upper lobe of the right lung. Computed tomographic scanning demonstrated that the mass was invading the posterior chest wall, but no mediastinal adenopathy was evident. Further computed tomographic scanning of the abdomen and pelvis showed no abnormalities. Results of testicular ultrasound examination were negative. Findings on routine laboratory chemistry profile including serum prolactin and thyroxine levels, complete blood count, and urinalysis were all unremarkable. The serum beta-human chorionic gonadotropin level was markedly elevated. Radioimmunoassay evaluation of the relevant steroid hormones is shown in Table I. Right upper lobectomy was performed after mediastinoscopy when
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TABLE
STUDIES
I
IN CHORIOCARCINOMA-WHITCOMB
ET AL
Serum Measurements Preoperative
Estradiol (pg/ml) Estrone (pg/ml) Testosterone (rig/ml) Androstenedione (rig/ml) Dehydroepiandrosterone sulfate (fig/ml) Beta-human chorionic gonadotropin (mlU/ml) Follicle-stimulating hormone (mlU/ml) Luteinizing hormone (mlU/ml)
48 Hours
100 455 16.7 35.3 3.1 344 <2 284
Postoperative 1 Week
2
Weeks
31.4 61.8 3.8 18.2
76.2
84.9
*
18.3 *
23.7 *
453 II *
190 * *
224 x x
Normal Male 5-25 5-25 4-10 0.5-2 1.9-3.8
* Not measured
lymph node sampling and frozen section examination of the nodes showed no tumor. Resection was carried out including removal of part of the posterior chest wall and the entire right upper lobe. The tissue margins were free of tumor by frozen section. Forty-eight hours postoperatively, the patient’s serum beta-human chorionic gonadotropin and sex steroid levels fell markedly (Table I). By 72 hours after surgery, less than 2 cm of gynecomastia could be palpated. Although the serum beta-human chorionic gonadotropin level continued to decrease, it was never undetectable and at two weeks after surgery began to rise. Computed tomographic scanning of the chest at this time showed a new left lower lobe lesion. Measurements of serum testosterone, androstenedione, estradiol, and estrone showed all except estrone elevated to near preoperative levels (Table I). It is noteworthy that the patient’s gynecomastia did not worsen with the appearance of the new pulmonary lesion. He is currently receiving chemotherapy. Pathologic study of the tumor showed it Tissue Studies. to be a choriocarcinoma. There were multiple areas of hemorrhage and necrosis within the tumor. Large multinucleated syncytiotrophoblasts were evident (Figure 1). Immunoperoxidase staining of the tumor demonstrated human
chorionic gonadotropin. Results of stains for luteinizing hormone, follicle-stimulating hormone, and thyrotropin were negative. Part of the resected tumor was placed in a saline/EDTA/ NADPH solution buffered to pH 7.4. A portion of uninvolved lung was handled similarly. Both specimens were homogenized and separated into mitochondrial, microsomal, and cytosolic fractions using methods previously described [4]. Quantitative enzyme assays for steroid 17,20-lyase, aromatase, and 17 alpha-hydroxylase were performed on the microsomal fractions [4,5]. Measurements of testosterone, androstenedione, estrone, and estradiol were performed on cytosolic fractions of tumor and uninvolved lung [6,7]. Beta-human chorionic gonadotropin determinations were similarly performed utilizing antibody SB-6 obtained from the National institutes of Health. Tumor levels of estradiol were over two times greater than those found in normal lung tissue, but estrone levels were not appreciably different when compared with normal lung (Table II). Testosterone and androstenedione levels were also more than twice as high as those detected in normal lung (Table II). Aromatose activity was easily demonstrated in the tumor, but 17,20-lyase and 17 alpha-hydroxylase activities were not significantly different from background activity. The activities of the same enzymes in normal lung tissue were similarly undetectable (Table II). COMMENTS Primary choriocarcinoma of the lung is a rare condition, a recent review of the literature having recorded less than 20 cases [8]. The initial impression after resection was that this was a primary lung tumor on the basis of the gross findings at surgery and our negative radiographic survey results. However, in view of the subsequent clinical course, it is more likely that the primary source was in the testes or mecfiastinum, undetectable by current radiologic techniques. It remains possible that the primary was in actuality the original resected mass and the recurrence represents a metastasis to the other lung. The majority of patients with choriocarcinoma have markedly elevated serum beta-human chorionic gonado-
Figure 1. Representative tumor section with multi-nucleated syncytiotrophoblast (hematoxylin and eosin stain; original magnification X 375, reduced by 30 percent).
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tropin levels with many being greater than one million mlU/ml [9]. Thyrotoxicosis is also a presenting symptom for some of these patients, particularly when their serum beta-human chorionic gonadotropin levels are greater than 100,000 mlU/ml [lo]. The cause of the hyperthyroid state is the structural similarity of the human chorionic gonadotropin molecule to the thyrotropin molecule with resultant stimulation of the thyroid gland. Despite these high serum gonadotropin levels, serum testosterone levels in most series are low or within the normal range whereas estrogen levels are usually markedly increased
TABLE
PI.
* Cytosolic protein. ’ pg substrate/mg microsomal i Undetectable. Values 31 SEM.
Our patient is unusual in having elevated serum androgen levels as well as increased levels of serum estrogens. Several possibilities exist as to why elevated serum betahuman chorionic gonadotropin levels do not usually proportionally increase androgen production in the majority of patients [9,11,12]. The tumor beta-human chorionic gonadotropin may be immunologically reactive but biologically relatively inactive as regards testicular stimulation. In view of the elevated serum androgen levels, it is apparent that our patient’s beta-human chorionic gonadotropin molecule possessed an unusually high degree of biologic activity. Another possibility for reduced serum testosterone levels is that the large amount of circulating betahuman chorionic gonadotropin interacts with testicular luteinizing hormone receptors with subsequent downregulation [13]. Human chorionic gonadotropin has been shown to induce a testicular steroidogenic desensitization with increasing plasma levels of beta-human chorionic gonadotropin [ 14,151. It has been hypothesized that part of this desensitization is through increased testicular estrogen production, considered by some to decrease C17,20-lyase activity [ 161. This latter mechanism could not have been a factor in our patient, as even with his high estrogen levels, androgen levels were also elevated, indicating no appreciable decrease in testicular 17,20-lyase activity. The question has arisen as to whether the tumor itself was capable of synthesizing the steroid hormones de novo independent of testicular activity [ 17,181. Kirschner et al [9] demonstrated that choriocarcinoma tissue was capable of converting tritiated dehydroepiandrosterone and dehydroepiandrosterone sulfate to estrone and estradiol using reverse isotope and crystallization techniques. Bahn et al [ 191 have shown that cultured choriocarcinoma cells behave like normal placenta in possessing aromatase activity but lack 17,20-lyase and 17 alpha-hydroxylase activity, both which are necessary for androgen synthesis. We were able to confirm the presence of aromatase activity in tumor extracts whereas none was detectable in normal lung. Similarly, no 17,20-lyase or 17 alpha-hyroxylase activity was found in tumor or in surrounding normal lung. The high tumor concentrations of
November
II
STUDIES IN CHORIOCARCINOMA-WHITCOMB
ET AL
Tissue Measurements Tumor
Estradiol(pg/mg protein*) Estrone (pg/mg protein*) Testosterone (pg/mg protein’) Androstenedione (pg/mg protein*) Beta-human chorionic gonadotropin (mlU/mg protein*) Aromatase activity+ Cl 7,204yase activity+ 17 alpha-hydroxylase activity+
180 f 3.6 37.8 f 0.8 222 f 15 689 f 23 1,590
NormalLung 71.8
f: 4.8
31.6 f 3.9 81.8 f 3.7 310 f 27 7.8 % % t
3.8 f 0.3 % %
protein/hour.
testosterone and androstenedione must therefore indicate that the tumor was able to concentrate these steroids. Thus, although the contribution of aromatase activity elsewhere cannot be assessed, it is likely that the bulk of the patient’s excess estrogen was derived from tumor conversion of androgen to estrogen. Although the activity per milligram of microsomal protein was modest, the total amount present would enable the tumor to produce more than 450 ng of estradiol per hour from testosterone. With placental aromatase, the Km for androstenedione is about three-fold lower than that for testosterone. Not only is androstenedione the preferred substrate, but it is an excellent inhibitor of the aromatization of testosterone [20]. The high serum concentration of estrone could be largely explained by conversion of testicular androstenedione to estrone by the tumor. In contrast, the serum estradiol concentration may be primarily a consequence of hepatic aromatization of testosterone. This conclusion is supported by the finding of an 86 percent reduction in serum estrone concentration within 48 hours of surgery and essentially a complete disappearance within seven days. Serum estradiol levels, on the other hand, fell 67 percent within 48 hours but quickly began to rise. Unexplained, however, is the lack of difference between tumor and normal lung cytosolic concentrations of estrone, whereas a clear difference in estradiol concentrations was apparent. The development of gynecomastia in patients with choriocarcinoma has been shown to be secondary to a decreased androgen/estrogen ratio [ 1,2]. This is generally a consequence of low to normal androgen production with a relative increase in estrogen production. Our patient is again unusual in that he had an increase in both serum androgen and estrogen levels yet had prominent gynecomastia, indicating that the concept of an altered ratio rather than any absolute level of either steroid remains valid. It would seem that the amount of increase in estrogen relative to androgen necessary to promote gyne-
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In summary, the evidence suggests that the choriocarcinoma was secreting beta-human chorionic gonadotropin of such high biologic activity that the patient’s testes produced excessive quantities of androgens. These steroids appeared to be concentrated within the tumor and aromatized to estrogens. The patient’s gynecomastia was related to the excess tumor-derived estrogens and the abnormal androgen/estrogen ratio, not to the absolute value of either class of steroid.
comastia in our patient was minimal. It is also of interest that this patient’s gynecomastia did not worsen with the appearance of a metastatic lesion. The only difference in the hormonal profile at the time of the recurrence was the very low serum estrone level compared with the markedly elevated levels present initially. It would appear that the stimulus for the gynecomastia was the sum total of estrone and estradiol relative to androgen rather than an absolute level of either estrogen.
REFERENCES 1.
5.
6.
8.
9.
10.
920
Siiteri PK, MacDonald PC: Role of extraglandular estrogen in human endocrinology. In: Greep RO, Astwood EB, eds. Handbook of physiology 7, endocrinology vol II. Washington: American Physiology Society, 1973; 615-629. McFayden IJH, Bulton AE, Cameron EHD, Hunter WM, Raab G, Forrest APM: Gonadal-pituitary hormone levels in gynecomastia. Clin Endocrinol (Oxf) 1980; 13: 77-86. Schimke RN, Madigan CM, Silver BJ, Favian CF, Stephens RL: Choriocarcinoma, thyrotoxicosis, and the Klinefelter syndrome. Cancer Genet Cytogenet 1083; 9: l-7. Johnson DC, Griswold T: Ovarian C17, 20-lyase: changes in intact and hypophysectomized immature rats treated with pregnant mare’s serum gonadotropin. J Steroid Biochem 1984; 20: 733-739. Johnson DC, Chon-Hwa T, Hoversland RC: Steroid 17-hydroxylase activity of ovarian granulosa cells from hypophysectomized immature rats treated with pregnant mare’s serum gonadotropin. Steroids 1081; 38: 581-592. Grotjan HE, Johnson DC: Response of the pituitary-testicular axis to luteinizing hormone-releasing hormone in the immature male rat. Acta Endocrinol (Copenh) 1977; 84: 254-267. Sashida T, Johnson DC: The response of the immature rat ovary to gonadotrophins: acute changes in cyclic-AMP, progesterone, testosterone, androstenedione, and oestradiol after treatment with PMS or FSH-FLH. Acta Endocrinol (Copenh) 1976; 82: 413-425. Zapatero J, Bellon J, Baamonde C, et al: Primary choriocarcinema of the lung: presentation of a case and review of the literature. Stand J Thorac Cardiovasc Surg 1982; 16: 279-281. Kirschner MA, Cohen FB, Jespersen D: Estrogen production and its origin in men with gonadotropin-producing neoplasms. J Clin Endocrinol Metab 1974; 30: 112-118. Norman FJ, Green-Thompson RW, Jialal I, Soutter WP, Pillary NL, Joubert SM: Hyperthyroidism in gestational tro-
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phoblastic neoplasm. Clin Endocrinol (Oxf) 1081; 15: 395-401. Weinstein RL, Kelch RP, Jenner MR, et al: Secretion of unconjugated androgens and estrogens by the normal and abnormal human testis before and after human chorionic gonadotropin. J Clin Invest 1974; 53: 1-6. Kirshner MA, Wider JA, Ross GT: Leydig cell function in men with gonadotropin-producing testicular tumors. J Clin Endocrinol Metab 1970; 30: 504-511. Haour F, Saez JM: hCG-dependent regulation of gonadotropin receptor sites: negative control in testicular Leydig cells. Mol Cell Endocrinol 1077; 7: 17-24. Saez JM, Forest MG: Kinetics of human chorionic gonadotropin-induced steroidogenic response of the human testis. I. Plasma testosterone: implications for human chorionic gonadotropin stimulation test. J Clin Endocrinol Metab 1079; 49: 278-283. Cigorraga SB, Dutan ML, Catt KJ: Regulation of luteinizing hormone receptors and steroidogenesis in gonadotropindesensitized Leydig cells. J Biol Chem 1978; 253: 42074304. Kalla NR, Nisula BC, Menard RH, Loriaux DL: Estrogen modulation of Leydig cell function (abstr). Endocrinology 1977; 100: (suppl) 82. Flury A, Genti-Raimondi S, Nowotomy E, Bialet-Tizeira JE, Sierra C, Patrito LC: Biosynthesis in vitro of human chorionic gonadotrophin and steroids from testicular tissue in man with choriocarcinoma. Ceil Mol Biol 1970; 25: 125120. Schut HAJ, Townsley JD: Oestrogen formation from Cl9 precursors in human choriocarcinoma in culture. Acta Endocrinol (Copenh) 1977; 84: 633-641. Bahn RS, Worsham A, Speeg KV, Ascoli M, Rabin D: Characterization of steroid production in cultured human choriocarcinoma cells. J Clin Endocrinol Metab 1981; 52: 447-450.
Pheochromocytoma Presenting with Prinzmetal’s Angina
THOMAS S. GOLDBAUM, M.D. STUART HENOCHOWICZ, M.D. MAHMOUD MUSTAFA, M.D. MICHAEL BLUNDA, M.D. JOSEPH LINDSAY, Jr., M.D., F.A.C.P. Washington,
D.C.
A patient with a pheochromocytoma presented with profound hypertension and the clinical syndrome of coronary artery spasm after the initiation of beta blockade therapy. It is postulated that intense unopposed alpha receptor stimulation can precipitate coronary artery spasm in susceptible persons with this tumor. Pheochromocytoma is known to produce multiple effects on the cardiovascular system, including intense peripheral vasoconstriction, hypertension (both paroxysmal and fixed), hypotension, “toxic niyocarditis,” myocardial fibrosis, sudden death, and possibly hypertrophic cardiomyopathy [l-4]. Symptoms and electrocardiographic changes suggestive of myocardial ischemia are frequent. ST segment depression, prominent U waves, and diffuse T wave abnormalities are common and have been attributed to catecholamine-induced myocarditis [5]. This report describes a patient with a pheochromocytoma who presented with hypertension, chest pain, and ST segment elevation following initiation of betaadrenergic blocker therapy. Obstructive corohary lesions were absent. We postulate spasm of one or more of the epicardial coronary arteries as the basis for this observation.
CASEREPORT
From the Department of Medicine, Washington Hospital Center, George Washington University School of Medicine, Washington, D.C. Requests for reorints should be addressed to Dr. Joseoh Lindsay, Jr., Department of Cardiology, Washington Hospital Center, 110 Irving Street N.W., Washington, D.C. 20010. Manuscript submitted May 22, 1985, and accepted July 16, 1985.
A 32-year-old woman was admitted because of chest pain and palpitation% She had experienced episodic headaches, flushing, sweating, nausea, and palpitations during the previous several months. Blood pressure of 240/140 mm Hg was noted three months prior to admission, and hydrochlorothiazide was prescribed. When the symptoms persisted, nadolol was prescribed. On admission, physical examination was remarkable for a pulse of 44, beats per minute and a blood pressure of 2381112 mm Hg. Electrocardiography revealed ST segment elevation in leads I and aVL, and ST segment depression in leads II, Ill, and aVF (Figure 1). The patient was treated with oral nifedipine, sublingual and intravenous nitroglycerin, and intravenous lidoCaine. The chest pain resolved, and her blood pressure and electrocardiographic abnormalities normalized. Serial serum creatine phosphokinase levels were within the normal range. Coronary arteriography revealed normal coronary arteries and normal left ventricular contractility. Urinary metanephrine and catecholamine concentrations were elevated, and computed tomographic scanning of the abdomen revealed a left adrenal mass. At surgery, a 3.5 by 2 by 1.5 cm pheochromocytoma was removed. Postoperatively, the patient has been free of chest pain, and her blood pressure has been normal.
COMMENTS As many as 75 percent of patients with pheochromocytoma have electrocardiographic abnormalities. ST depression, marked T wave inversion, prolonged Q-T interval, left ventricular hypertrophy, bundle
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PHEOCHROMOCYTOMA
AND PRINZMETAL’S
2
ANGINA-GOLDBAUM
3
avR
ET AL
ad
avl
)
Figure 1. Electrocardiographic recoraF ing during her episode of chest pain.
this to be the case in our patient. Further, we believe that the administration of a betaadrenergic blocking drug prior to the onset of her myocardial ischemic syndrome may have provoked spasm by removing beta receptor tone and leaving the alpha effects of circulating catecholamines relatively unopposed.
branch block, and supraventricular ectopic beats have been reported [S]. On the other hand, ST segment elevation has only rarely been detected [l-3,6]. Postmortem findings in three patients with ST segment elevation have been reported. Neither epicardial coronary artery disease nor discrete areas of myocardial necrosis were found in these patients. Inflammatory cell infiltration and myocardial fiber degeneration were demonstrated, and “toxic myocarditis” was thought to account for the ST segment abnormality [ 1,3,6]. In addition to typical symptoms of pheochromocytoma, our patient’s illness was highlighted by chest pain characteristic of myocardial ischemia accompanied by transient ST segment elevation. She had no evidence of myocardial necrosis on serial electrocardiographic and serum enzyme examinations, and she had neither asynergy nor obstructive coronary artery disease on catheterization. We propose that coronary artery spasm best explains these findings. Angiographic evidence of spasm in peripheral arteries of patients with pheochromocytoma has been reported [2]. McGonigle and his associates [7] first suggested coronary artery spasm as the cause of ST segment elevation in a patient who experienced chest pain and myocardial infarction. Subsequently, normal coronary arteries were demonstrated angiographically. There is substantial evidence that the epicardial coronary arteries are under the influence of both alpha and beta sympathetic tone, but the relationship of this innervation to coronary spasm is incompletely understood [8]. There are, however, clinical observations that suggest that alpha-adrenergic stirhulation [9] or beta-adrenergic blockade [lo] may precipitate or promote spasm in susceptible persons. It follows that this could occur in susceptible patients with pheochromocytoma. We believe
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REFiiRENCES 1.
2.
3. 4. 5.
6.
7.
8.
9.
10.
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Van Vliet PD, Burchell HB, Titus JL: Focal myocarditis associated with pheochromocytoma. N Engl J Med 1966; 274: 1102-1108. Radtke WE, Kazmier FJ, Rutherford BD, Sheps SG: Cardiovascular complications of pheochromocytoma crisis. Am J Cardiol 1975; 35: 701-705. Manger WM, Gifford RW: Pheochromdcytoma. New York: Springer-Verlag, 1977; 184-191. Priest WM: Pheochromocytoma with fatal myocardial infarction in a man aged 22. Br Med J 1952; 2: 860-862. Surawicz B, Margiard ML: Electrocardiogram in endocrine and metabolic disorders. In: Rios JC, ed. Clinical electrocardiographic correlations. Philadelphia: FA Davis, 1977; 243-266. Pelkonen R, Pitkanen E: Unusual electrocardiographic changes in pheochromocytoma. Acta Med Stand 1963; 173: 41-44. McGonigle P, Webb SW, Adgoy AA: Pheochromocytoma: an unusuai cause of chest pain. Br Med J 1983; 286: 14771478. Yasue H, Touyama M, Shimamoto Mi Kato H, Tanaka S, Akiyanma F: Role of autonomic nervous system in the pathogenesis of Prinzmetal’s variant form of angina. Circulation 1974; 50: 534-539. Yasue H, Touyama M. Kato H, Tariaka S, Akiyama F: Prinzmetal’s variant form of angina as a manifestation of alreceptor-mediated coronary artery pha-adrenergic spasm: documented by coronary arteriography. Am Heart J 1978; 91: 148-155, Robertson RM, Wood AJJ, Vaughn WK, Robertson b: Exacerbation of vasotonic angina pectoris by propranolol. Circulation 1982; 65: 281-285.
RANDALL W. WHITCOMB, M.D.* R. NEIL SCHIMKE, M.D. JOSEPH L. KYNER, M.D. BARBARA P. LUKERT, M.D. DONALD C. JOHNSON, Ph.D. Kansas City, Kansas
Sex hormone profiles were studied in serum and tumor extracts of a man with pulmonary choriocarcinoma and gynecomastia. Although levels of serum estrogens were elevated as expected, serum androgen levels were uncharacteristically quite high. Tumor extract contained increased quantities of both androgens and estrogens when compared with surrounding normal lung tissue, but lacked the enzymes necessary for androgen biosynthesis while retaining aromatase activity. It is concluded that unlike the usual male patient with choriocarcinoma, the tumor-derived beta-human chorionic gonadotropin stimulated testicular androgen production. These androgens were in turn concentrated by the tumor and converted in part to estrogens. Furthermore, gynecoma&a can occur even in the face of high serum androgen concentrations provided total estrogen levels are also disproportionately elevated. Male patients with choriocarcinoma often first present with gynecomastia. The gynecomastia is generally considered to be secondary to a decreased androgenjestrogen ratio [ 1,2], but the reason for this alteration in nontesticular tumors is not always clear. In a number of instances, the gynecomastia has been long-standing and the patient was found to have the Klinefelter syndrome, a condition that seems to predispose to extragonadal germ cell tumors [3]. Because of the apparent uncertainties about steroid metabolism in male patients with germ cell tumors, we studied tumor and tumor extracts from a 46,XY patient with choriocarcinoma.
CASEREPORT
From the Division of Endocrinology, Metabolism and Genetics, Department of Internal Medicine and the Department of Physiology, University of Kansas School of Medicine, Kansas City, Kansas. This work was supported in part by the Hinman fund. Requests for reprints should be addressed to Dr. R. Neil Schimke, Department of Medicine, University of Kansas School of Medicine, 39th and Rainbow Boulevard, Kansas City, Kansas 66103. Manuscript submitted May 9, 1985, and accepted July 9, 1985. *Current address: National Institutes of Health, Building 10, Room lON262, Bethesda, Maryland 20892.
A 41-year-old man presented with a two-week history of painful bilateral gynecomastia. He specifically denied having galactorrhea. There was no significant past medical history and he was taking no medications. On physical examination, 3 to 4 cm of glandular breast tissue could be palpated bilaterally. Results of the remainder of the physical examination were unremarkable including careful testicular palpation. Chest radiography showed a 5 cm mass in the upper lobe of the right lung. Computed tomographic scanning demonstrated that the mass was invading the posterior chest wall, but no mediastinal adenopathy was evident. Further computed tomographic scanning of the abdomen and pelvis showed no abnormalities. Results of testicular ultrasound examination were negative. Findings on routine laboratory chemistry profile including serum prolactin and thyroxine levels, complete blood count, and urinalysis were all unremarkable. The serum beta-human chorionic gonadotropin level was markedly elevated. Radioimmunoassay evaluation of the relevant steroid hormones is shown in Table I. Right upper lobectomy was performed after mediastinoscopy when
November 1966
The American Journal of Medicine
Volume 61
917
ENDOCRINE
TABLE
STUDIES
I
IN CHORIOCARCINOMA-WHITCOMB
ET AL
Serum Measurements Preoperative
Estradiol (pg/ml) Estrone (pg/ml) Testosterone (rig/ml) Androstenedione (rig/ml) Dehydroepiandrosterone sulfate (fig/ml) Beta-human chorionic gonadotropin (mlU/ml) Follicle-stimulating hormone (mlU/ml) Luteinizing hormone (mlU/ml)
48 Hours
100 455 16.7 35.3 3.1 344 <2 284
Postoperative 1 Week
2
Weeks
31.4 61.8 3.8 18.2
76.2
84.9
*
18.3 *
23.7 *
453 II *
190 * *
224 x x
Normal Male 5-25 5-25 4-10 0.5-2 1.9-3.8
* Not measured
lymph node sampling and frozen section examination of the nodes showed no tumor. Resection was carried out including removal of part of the posterior chest wall and the entire right upper lobe. The tissue margins were free of tumor by frozen section. Forty-eight hours postoperatively, the patient’s serum beta-human chorionic gonadotropin and sex steroid levels fell markedly (Table I). By 72 hours after surgery, less than 2 cm of gynecomastia could be palpated. Although the serum beta-human chorionic gonadotropin level continued to decrease, it was never undetectable and at two weeks after surgery began to rise. Computed tomographic scanning of the chest at this time showed a new left lower lobe lesion. Measurements of serum testosterone, androstenedione, estradiol, and estrone showed all except estrone elevated to near preoperative levels (Table I). It is noteworthy that the patient’s gynecomastia did not worsen with the appearance of the new pulmonary lesion. He is currently receiving chemotherapy. Pathologic study of the tumor showed it Tissue Studies. to be a choriocarcinoma. There were multiple areas of hemorrhage and necrosis within the tumor. Large multinucleated syncytiotrophoblasts were evident (Figure 1). Immunoperoxidase staining of the tumor demonstrated human
chorionic gonadotropin. Results of stains for luteinizing hormone, follicle-stimulating hormone, and thyrotropin were negative. Part of the resected tumor was placed in a saline/EDTA/ NADPH solution buffered to pH 7.4. A portion of uninvolved lung was handled similarly. Both specimens were homogenized and separated into mitochondrial, microsomal, and cytosolic fractions using methods previously described [4]. Quantitative enzyme assays for steroid 17,20-lyase, aromatase, and 17 alpha-hydroxylase were performed on the microsomal fractions [4,5]. Measurements of testosterone, androstenedione, estrone, and estradiol were performed on cytosolic fractions of tumor and uninvolved lung [6,7]. Beta-human chorionic gonadotropin determinations were similarly performed utilizing antibody SB-6 obtained from the National institutes of Health. Tumor levels of estradiol were over two times greater than those found in normal lung tissue, but estrone levels were not appreciably different when compared with normal lung (Table II). Testosterone and androstenedione levels were also more than twice as high as those detected in normal lung (Table II). Aromatose activity was easily demonstrated in the tumor, but 17,20-lyase and 17 alpha-hydroxylase activities were not significantly different from background activity. The activities of the same enzymes in normal lung tissue were similarly undetectable (Table II). COMMENTS Primary choriocarcinoma of the lung is a rare condition, a recent review of the literature having recorded less than 20 cases [8]. The initial impression after resection was that this was a primary lung tumor on the basis of the gross findings at surgery and our negative radiographic survey results. However, in view of the subsequent clinical course, it is more likely that the primary source was in the testes or mecfiastinum, undetectable by current radiologic techniques. It remains possible that the primary was in actuality the original resected mass and the recurrence represents a metastasis to the other lung. The majority of patients with choriocarcinoma have markedly elevated serum beta-human chorionic gonado-
Figure 1. Representative tumor section with multi-nucleated syncytiotrophoblast (hematoxylin and eosin stain; original magnification X 375, reduced by 30 percent).
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tropin levels with many being greater than one million mlU/ml [9]. Thyrotoxicosis is also a presenting symptom for some of these patients, particularly when their serum beta-human chorionic gonadotropin levels are greater than 100,000 mlU/ml [lo]. The cause of the hyperthyroid state is the structural similarity of the human chorionic gonadotropin molecule to the thyrotropin molecule with resultant stimulation of the thyroid gland. Despite these high serum gonadotropin levels, serum testosterone levels in most series are low or within the normal range whereas estrogen levels are usually markedly increased
TABLE
PI.
* Cytosolic protein. ’ pg substrate/mg microsomal i Undetectable. Values 31 SEM.
Our patient is unusual in having elevated serum androgen levels as well as increased levels of serum estrogens. Several possibilities exist as to why elevated serum betahuman chorionic gonadotropin levels do not usually proportionally increase androgen production in the majority of patients [9,11,12]. The tumor beta-human chorionic gonadotropin may be immunologically reactive but biologically relatively inactive as regards testicular stimulation. In view of the elevated serum androgen levels, it is apparent that our patient’s beta-human chorionic gonadotropin molecule possessed an unusually high degree of biologic activity. Another possibility for reduced serum testosterone levels is that the large amount of circulating betahuman chorionic gonadotropin interacts with testicular luteinizing hormone receptors with subsequent downregulation [13]. Human chorionic gonadotropin has been shown to induce a testicular steroidogenic desensitization with increasing plasma levels of beta-human chorionic gonadotropin [ 14,151. It has been hypothesized that part of this desensitization is through increased testicular estrogen production, considered by some to decrease C17,20-lyase activity [ 161. This latter mechanism could not have been a factor in our patient, as even with his high estrogen levels, androgen levels were also elevated, indicating no appreciable decrease in testicular 17,20-lyase activity. The question has arisen as to whether the tumor itself was capable of synthesizing the steroid hormones de novo independent of testicular activity [ 17,181. Kirschner et al [9] demonstrated that choriocarcinoma tissue was capable of converting tritiated dehydroepiandrosterone and dehydroepiandrosterone sulfate to estrone and estradiol using reverse isotope and crystallization techniques. Bahn et al [ 191 have shown that cultured choriocarcinoma cells behave like normal placenta in possessing aromatase activity but lack 17,20-lyase and 17 alpha-hydroxylase activity, both which are necessary for androgen synthesis. We were able to confirm the presence of aromatase activity in tumor extracts whereas none was detectable in normal lung. Similarly, no 17,20-lyase or 17 alpha-hyroxylase activity was found in tumor or in surrounding normal lung. The high tumor concentrations of
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STUDIES IN CHORIOCARCINOMA-WHITCOMB
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Tissue Measurements Tumor
Estradiol(pg/mg protein*) Estrone (pg/mg protein*) Testosterone (pg/mg protein’) Androstenedione (pg/mg protein*) Beta-human chorionic gonadotropin (mlU/mg protein*) Aromatase activity+ Cl 7,204yase activity+ 17 alpha-hydroxylase activity+
180 f 3.6 37.8 f 0.8 222 f 15 689 f 23 1,590
NormalLung 71.8
f: 4.8
31.6 f 3.9 81.8 f 3.7 310 f 27 7.8 % % t
3.8 f 0.3 % %
protein/hour.
testosterone and androstenedione must therefore indicate that the tumor was able to concentrate these steroids. Thus, although the contribution of aromatase activity elsewhere cannot be assessed, it is likely that the bulk of the patient’s excess estrogen was derived from tumor conversion of androgen to estrogen. Although the activity per milligram of microsomal protein was modest, the total amount present would enable the tumor to produce more than 450 ng of estradiol per hour from testosterone. With placental aromatase, the Km for androstenedione is about three-fold lower than that for testosterone. Not only is androstenedione the preferred substrate, but it is an excellent inhibitor of the aromatization of testosterone [20]. The high serum concentration of estrone could be largely explained by conversion of testicular androstenedione to estrone by the tumor. In contrast, the serum estradiol concentration may be primarily a consequence of hepatic aromatization of testosterone. This conclusion is supported by the finding of an 86 percent reduction in serum estrone concentration within 48 hours of surgery and essentially a complete disappearance within seven days. Serum estradiol levels, on the other hand, fell 67 percent within 48 hours but quickly began to rise. Unexplained, however, is the lack of difference between tumor and normal lung cytosolic concentrations of estrone, whereas a clear difference in estradiol concentrations was apparent. The development of gynecomastia in patients with choriocarcinoma has been shown to be secondary to a decreased androgen/estrogen ratio [ 1,2]. This is generally a consequence of low to normal androgen production with a relative increase in estrogen production. Our patient is again unusual in that he had an increase in both serum androgen and estrogen levels yet had prominent gynecomastia, indicating that the concept of an altered ratio rather than any absolute level of either steroid remains valid. It would seem that the amount of increase in estrogen relative to androgen necessary to promote gyne-
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In summary, the evidence suggests that the choriocarcinoma was secreting beta-human chorionic gonadotropin of such high biologic activity that the patient’s testes produced excessive quantities of androgens. These steroids appeared to be concentrated within the tumor and aromatized to estrogens. The patient’s gynecomastia was related to the excess tumor-derived estrogens and the abnormal androgen/estrogen ratio, not to the absolute value of either class of steroid.
comastia in our patient was minimal. It is also of interest that this patient’s gynecomastia did not worsen with the appearance of a metastatic lesion. The only difference in the hormonal profile at the time of the recurrence was the very low serum estrone level compared with the markedly elevated levels present initially. It would appear that the stimulus for the gynecomastia was the sum total of estrone and estradiol relative to androgen rather than an absolute level of either estrogen.
REFERENCES 1.
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Siiteri PK, MacDonald PC: Role of extraglandular estrogen in human endocrinology. In: Greep RO, Astwood EB, eds. Handbook of physiology 7, endocrinology vol II. Washington: American Physiology Society, 1973; 615-629. McFayden IJH, Bulton AE, Cameron EHD, Hunter WM, Raab G, Forrest APM: Gonadal-pituitary hormone levels in gynecomastia. Clin Endocrinol (Oxf) 1980; 13: 77-86. Schimke RN, Madigan CM, Silver BJ, Favian CF, Stephens RL: Choriocarcinoma, thyrotoxicosis, and the Klinefelter syndrome. Cancer Genet Cytogenet 1083; 9: l-7. Johnson DC, Griswold T: Ovarian C17, 20-lyase: changes in intact and hypophysectomized immature rats treated with pregnant mare’s serum gonadotropin. J Steroid Biochem 1984; 20: 733-739. Johnson DC, Chon-Hwa T, Hoversland RC: Steroid 17-hydroxylase activity of ovarian granulosa cells from hypophysectomized immature rats treated with pregnant mare’s serum gonadotropin. Steroids 1081; 38: 581-592. Grotjan HE, Johnson DC: Response of the pituitary-testicular axis to luteinizing hormone-releasing hormone in the immature male rat. Acta Endocrinol (Copenh) 1977; 84: 254-267. Sashida T, Johnson DC: The response of the immature rat ovary to gonadotrophins: acute changes in cyclic-AMP, progesterone, testosterone, androstenedione, and oestradiol after treatment with PMS or FSH-FLH. Acta Endocrinol (Copenh) 1976; 82: 413-425. Zapatero J, Bellon J, Baamonde C, et al: Primary choriocarcinema of the lung: presentation of a case and review of the literature. Stand J Thorac Cardiovasc Surg 1982; 16: 279-281. Kirschner MA, Cohen FB, Jespersen D: Estrogen production and its origin in men with gonadotropin-producing neoplasms. J Clin Endocrinol Metab 1974; 30: 112-118. Norman FJ, Green-Thompson RW, Jialal I, Soutter WP, Pillary NL, Joubert SM: Hyperthyroidism in gestational tro-
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phoblastic neoplasm. Clin Endocrinol (Oxf) 1081; 15: 395-401. Weinstein RL, Kelch RP, Jenner MR, et al: Secretion of unconjugated androgens and estrogens by the normal and abnormal human testis before and after human chorionic gonadotropin. J Clin Invest 1974; 53: 1-6. Kirshner MA, Wider JA, Ross GT: Leydig cell function in men with gonadotropin-producing testicular tumors. J Clin Endocrinol Metab 1970; 30: 504-511. Haour F, Saez JM: hCG-dependent regulation of gonadotropin receptor sites: negative control in testicular Leydig cells. Mol Cell Endocrinol 1077; 7: 17-24. Saez JM, Forest MG: Kinetics of human chorionic gonadotropin-induced steroidogenic response of the human testis. I. Plasma testosterone: implications for human chorionic gonadotropin stimulation test. J Clin Endocrinol Metab 1079; 49: 278-283. Cigorraga SB, Dutan ML, Catt KJ: Regulation of luteinizing hormone receptors and steroidogenesis in gonadotropindesensitized Leydig cells. J Biol Chem 1978; 253: 42074304. Kalla NR, Nisula BC, Menard RH, Loriaux DL: Estrogen modulation of Leydig cell function (abstr). Endocrinology 1977; 100: (suppl) 82. Flury A, Genti-Raimondi S, Nowotomy E, Bialet-Tizeira JE, Sierra C, Patrito LC: Biosynthesis in vitro of human chorionic gonadotrophin and steroids from testicular tissue in man with choriocarcinoma. Ceil Mol Biol 1970; 25: 125120. Schut HAJ, Townsley JD: Oestrogen formation from Cl9 precursors in human choriocarcinoma in culture. Acta Endocrinol (Copenh) 1977; 84: 633-641. Bahn RS, Worsham A, Speeg KV, Ascoli M, Rabin D: Characterization of steroid production in cultured human choriocarcinoma cells. J Clin Endocrinol Metab 1981; 52: 447-450.
Pheochromocytoma Presenting with Prinzmetal’s Angina
THOMAS S. GOLDBAUM, M.D. STUART HENOCHOWICZ, M.D. MAHMOUD MUSTAFA, M.D. MICHAEL BLUNDA, M.D. JOSEPH LINDSAY, Jr., M.D., F.A.C.P. Washington,
D.C.
A patient with a pheochromocytoma presented with profound hypertension and the clinical syndrome of coronary artery spasm after the initiation of beta blockade therapy. It is postulated that intense unopposed alpha receptor stimulation can precipitate coronary artery spasm in susceptible persons with this tumor. Pheochromocytoma is known to produce multiple effects on the cardiovascular system, including intense peripheral vasoconstriction, hypertension (both paroxysmal and fixed), hypotension, “toxic niyocarditis,” myocardial fibrosis, sudden death, and possibly hypertrophic cardiomyopathy [l-4]. Symptoms and electrocardiographic changes suggestive of myocardial ischemia are frequent. ST segment depression, prominent U waves, and diffuse T wave abnormalities are common and have been attributed to catecholamine-induced myocarditis [5]. This report describes a patient with a pheochromocytoma who presented with hypertension, chest pain, and ST segment elevation following initiation of betaadrenergic blocker therapy. Obstructive corohary lesions were absent. We postulate spasm of one or more of the epicardial coronary arteries as the basis for this observation.
CASEREPORT
From the Department of Medicine, Washington Hospital Center, George Washington University School of Medicine, Washington, D.C. Requests for reorints should be addressed to Dr. Joseoh Lindsay, Jr., Department of Cardiology, Washington Hospital Center, 110 Irving Street N.W., Washington, D.C. 20010. Manuscript submitted May 22, 1985, and accepted July 16, 1985.
A 32-year-old woman was admitted because of chest pain and palpitation% She had experienced episodic headaches, flushing, sweating, nausea, and palpitations during the previous several months. Blood pressure of 240/140 mm Hg was noted three months prior to admission, and hydrochlorothiazide was prescribed. When the symptoms persisted, nadolol was prescribed. On admission, physical examination was remarkable for a pulse of 44, beats per minute and a blood pressure of 2381112 mm Hg. Electrocardiography revealed ST segment elevation in leads I and aVL, and ST segment depression in leads II, Ill, and aVF (Figure 1). The patient was treated with oral nifedipine, sublingual and intravenous nitroglycerin, and intravenous lidoCaine. The chest pain resolved, and her blood pressure and electrocardiographic abnormalities normalized. Serial serum creatine phosphokinase levels were within the normal range. Coronary arteriography revealed normal coronary arteries and normal left ventricular contractility. Urinary metanephrine and catecholamine concentrations were elevated, and computed tomographic scanning of the abdomen revealed a left adrenal mass. At surgery, a 3.5 by 2 by 1.5 cm pheochromocytoma was removed. Postoperatively, the patient has been free of chest pain, and her blood pressure has been normal.
COMMENTS As many as 75 percent of patients with pheochromocytoma have electrocardiographic abnormalities. ST depression, marked T wave inversion, prolonged Q-T interval, left ventricular hypertrophy, bundle
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ad
avl
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Figure 1. Electrocardiographic recoraF ing during her episode of chest pain.
this to be the case in our patient. Further, we believe that the administration of a betaadrenergic blocking drug prior to the onset of her myocardial ischemic syndrome may have provoked spasm by removing beta receptor tone and leaving the alpha effects of circulating catecholamines relatively unopposed.
branch block, and supraventricular ectopic beats have been reported [S]. On the other hand, ST segment elevation has only rarely been detected [l-3,6]. Postmortem findings in three patients with ST segment elevation have been reported. Neither epicardial coronary artery disease nor discrete areas of myocardial necrosis were found in these patients. Inflammatory cell infiltration and myocardial fiber degeneration were demonstrated, and “toxic myocarditis” was thought to account for the ST segment abnormality [ 1,3,6]. In addition to typical symptoms of pheochromocytoma, our patient’s illness was highlighted by chest pain characteristic of myocardial ischemia accompanied by transient ST segment elevation. She had no evidence of myocardial necrosis on serial electrocardiographic and serum enzyme examinations, and she had neither asynergy nor obstructive coronary artery disease on catheterization. We propose that coronary artery spasm best explains these findings. Angiographic evidence of spasm in peripheral arteries of patients with pheochromocytoma has been reported [2]. McGonigle and his associates [7] first suggested coronary artery spasm as the cause of ST segment elevation in a patient who experienced chest pain and myocardial infarction. Subsequently, normal coronary arteries were demonstrated angiographically. There is substantial evidence that the epicardial coronary arteries are under the influence of both alpha and beta sympathetic tone, but the relationship of this innervation to coronary spasm is incompletely understood [8]. There are, however, clinical observations that suggest that alpha-adrenergic stirhulation [9] or beta-adrenergic blockade [lo] may precipitate or promote spasm in susceptible persons. It follows that this could occur in susceptible patients with pheochromocytoma. We believe
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Van Vliet PD, Burchell HB, Titus JL: Focal myocarditis associated with pheochromocytoma. N Engl J Med 1966; 274: 1102-1108. Radtke WE, Kazmier FJ, Rutherford BD, Sheps SG: Cardiovascular complications of pheochromocytoma crisis. Am J Cardiol 1975; 35: 701-705. Manger WM, Gifford RW: Pheochromdcytoma. New York: Springer-Verlag, 1977; 184-191. Priest WM: Pheochromocytoma with fatal myocardial infarction in a man aged 22. Br Med J 1952; 2: 860-862. Surawicz B, Margiard ML: Electrocardiogram in endocrine and metabolic disorders. In: Rios JC, ed. Clinical electrocardiographic correlations. Philadelphia: FA Davis, 1977; 243-266. Pelkonen R, Pitkanen E: Unusual electrocardiographic changes in pheochromocytoma. Acta Med Stand 1963; 173: 41-44. McGonigle P, Webb SW, Adgoy AA: Pheochromocytoma: an unusuai cause of chest pain. Br Med J 1983; 286: 14771478. Yasue H, Touyama M, Shimamoto Mi Kato H, Tanaka S, Akiyanma F: Role of autonomic nervous system in the pathogenesis of Prinzmetal’s variant form of angina. Circulation 1974; 50: 534-539. Yasue H, Touyama M. Kato H, Tariaka S, Akiyama F: Prinzmetal’s variant form of angina as a manifestation of alreceptor-mediated coronary artery pha-adrenergic spasm: documented by coronary arteriography. Am Heart J 1978; 91: 148-155, Robertson RM, Wood AJJ, Vaughn WK, Robertson b: Exacerbation of vasotonic angina pectoris by propranolol. Circulation 1982; 65: 281-285.