Taylor & Francis Taylor & Francis Group
POSTGRADUATE MEDICINE
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THE NEW 1951 SURGICAL FORUM VOLUME
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Adrenal Cortical Carcinoma with Excess Androgen Production in an Adult Man
William J. Kerr & Gilbert S. Gordan
To cite this article: William J. Kerr & Gilbert S. Gordan (1952) Adrenal Cortical Carcinoma with Excess Androgen Production in an Adult Man, Postgraduate Medicine, 11:4, 278-283, DOI: 10.1080/00325481.1952.11694248
To link to this article: http://dx.doi.org/10.1080/00325481.1952.11694248
Published online: 18 Apr 2016.
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ADRENAL CORTICAL CARCINOMA WITH EXCESS ANDROGEN PRODUCTION IN AN ADULT MAN
WILLIAM J. KERR AND GILBERT S. GORDAN UNIVERSITY OF CALIFORNIA SCHOOL OF MEDICINE, SAN FRANCISCO
T HE patient with an excess or deficiency of one or more hormones presents a diagnos- tic challenge to the clinician. The problem may be simple or difficult, depending upon how much is known of the specific actions in man of the hormones in question. The situation involves many factors, including patient’s age at onset, sex, racial and familial characteristics, nutritional state, environmental factors too numerous to mention, and variations in indi- vidual responses.
When excessive androgenic steroidal hor- mones are liberated, manifold clinical syndromes may present themselves, depending primarily on the age and sex of the patient. If this overpro- duction begins prenatally in female subjects (congenital adrenal cortical hyperplasia), the clinical syndrome known as female pseudo- hermaphroditism is found.1 The same hormonal anomaly originating postnatally in the pre- adolescent girl is perhaps best described as pseudosexual precocity.2 In the preadolescent boy, a condition of precocious puberty accom- panied by “infant Hercules” characteristics is the clinical manifestation of this same excess of adrenal or testicular androgens.3-8 In the adult female, excess androgen production of adrenal or ovarian origin results in virilism.º Excessive androgen production in the adult male is ex-
From the Division of Medicine, University of California School of Medicine, San Francisco, California.
ceedingly rare, having been reported in associa- tion with interstitial cell tumors of the testis in only four instances.10-13#
It is the purpose of this paper to report a simi- lar syndrome in an adult male, with the distinc- tion that the source of androgen in this patient was an adrenal cortical carcinoma, and to stress its anabolic consequences.
CASE REPORT
The patient, a 44 year old married man and father of two children, was referred to one of us (W. J. K.) by Dr. G. S. Delamere of Marys- ville, California. He entered the University of
*Budd’s case,13 although described as an interstitial cell tumor, was associated with production of estrogen and may have been a Sertoli cell tumor.
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California Hospital in January 1942, because of an upper abdominal mass noticed two months previously. He had been in good health until six months earlier, when he had developed nausea, postprandial abdominal discomfort, and severe weight loss from an accustomed 205 pounds to 145 pounds. X-ray studies had demon- strated a duodenal ulcer, and the patient had been treated with diet and powders, with good results. His symptoms disappeared; he again felt well and was able to eat all types of food without discomfort. His weight stabilized at 168 pounds. After the abdominal mass was first noted in December 1941, a laparotomy done elsewhere disclosed a large, doughy, vascular tumor filling the entire right upper quadrant. A biopsy was reported to show carcinoma of uncertain origin, and the patient entered the University of California Hospital for roent- genotherapy.
Upon examination, a large, firm, nontender mass was found below the right costal margin. Both breasts were enlarged and tender, but no secretion could be expressed. There was no lymphadenopathy and a rectal examination dis- closed a normal-sized prostate. Testes were of normal size and consistency; there were no abnormalities of voice, hair or pigmentation. Blood pressure was 135/85. The remainder of the examination disclosed nothing unusual, and revealed only alopecia capitis and an old right facial palsy.
Laboratory tests-Blood count: hemoglobin
12.2 gm .; RBC 4,360,000; WBC 10,000 per cubic millimeter with a normal differential count. Urine: normal. Stool: negative for occult blood. Icterus index 5.0. Rose bengal and intravenous galactose tolerance tests for liver function were normal. Phenolsulfonphthalein excretion test for renal function showed 77 per cent in two hours. X-ray films showed no abnormalities. Intravenous pyelograms (Figure 1) showed a large mass in the right upper quadrant displac- ing the kidney downward.
X-ray therapy was administered by Dr. R. S. Stone with the delivery of 3,650 r. in air to each of three portals. (Calculated dose in the tumor, 5,058 r.) The mass decreased in size. The patient felt well and strong and returned to work, but his breasts continued to enlarge. Libido, potency and shaving habits remained normal. Data con- cerning weight, hemoglobin and blood pressure are summarized below.
| DATE | WEIGHT (pounds) | HEMOGLOBIN (gm.) | BLOOD PRESSURE mm. of mercury |
|---|---|---|---|
| January 1942 | 168 | 12.2 | 135/85 |
| August 1942 | 170 | ||
| March 1943 | 176 | 13.1 | |
| January 1944 | 185 | ||
| January 1945 | 190 | 170/100 | |
| January 1946 | 15.9 | ||
| February 1946 | 180 | 13.9 | 170/100 |
| April 1946 | 180 | 16.6 | 195/125 |
| August 1946 | 197 | 17.4 | 230/130 |
| January 1947 | 220/130 | ||
| April 1947 | 18.1 | 220/140 | |
| May 1947 | 191 | 15.2 | 220/120 |
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TT will be noted that over a period of five years I the patient gained weight, his hemoglobin rose to polycythemic levels, and hypertension appeared. In February 1943, the patient had pneumonia and lost 20 pounds, but he quickly regained the lost weight. In September 1943, a rectal examination once more disclosed that the prostate was of normal size. In January 1945, it was found that the patient had hypertension. In January 1946, he had an episode of bleeding from his ulcer and lost a little weight, but re- gained it quickly on a bland diet. At this time an x-ray film of the chest (Figure 2) showed numerous dense masses in the lungs. It is of interest that the pulmonary masses were first detected in the course of a minifilm survey for tuberculosis at a time when the patient felt well and was working on a full schedule. X-ray therapy (approximately 800 r. in air through each of three portals) was delivered to a portion of the right side of the chest, but the masses progressed in size and number (Figure 3).
In April 1947, the patient complained of fail- ing vision, headaches and dyspnea, and was found to have hypertensive retinitis with papil- ledema (Keith-Wagener IV). Examination again showed gynecomastia and normal-sized prostate and testes, but there was now a vari- cocele on the right side. The heart was enlarged to the left, the blood pressure was 220/120, and bilateral ankle edema was present. X-ray exam- ination of the chest (Figure 4) showed progres- sion in the number and size of the pulmonary masses.
The patient’s symptoms were partially con-
trolled by frequent lumbar punctures with re- duction of the cerebrospinal pressure from 230 to 100 mm. of water. Assay of urinary 17-keto- steroids (ketonic fraction) showed an excretion of 224.5 mg. per day (10 times normal).
The patient continued to be active until October 1947, six years after the onset of symp- toms, when he lapsed into coma and died.
Postmortem examination by Dr. J. F. Mc- Kenna-At autopsy, a large tumor was found arising from the right adrenal with extension to the right kidney and metastases to the liver, diaphragm and lungs. On histologic examina- tion, the tumor cells were found to be large, with abundant pale, eosinophilic, granular cyto- plasm (Figure 5). The right adrenal cortex had been completely replaced by the tumor mass. The left adrenal appeared normal and was not atrophic.
The breast enlargement was found to be as- sociated with hypertrophy of the ductal system and especially of the periductal stroma (Figure 6). No acinar lobules were noted.
The testes were of normal size and histologi- cally appeared well within normal limits. Sper- matogenesis was seen to be in active progress (Figure 7). There was a slight increase in thick- ness of the basement membrane of the tubules and little, if any, reduction in number of the interstitial cells. The prostate was normal. The pituitary showed a moderate increase in eosino- phils but was otherwise normal.
Hypertensive changes were found in the heart, blood vessels and brain. The right kidney had been compressed by the large tumor mass
which had encroached upon the right renal artery and which had occluded the pelvis on that side. The right kidney was atrophic and histologically appeared ischemic with few eryth- rocytes in the glomerular capillaries (Figure 8). While the left kidney showed marked arterial and arteriolar subendothelial thickening, there was but moderate subintimal thickening of the smaller arteries in the right kidney. Scarring from a healed duodenal ulcer was identified.
DISCUSSION
Adrenal cortical tumors may be nonendocrine in the sense that they cause no hormonal effects, or they may result in specific clinical syndromes determined by the type of hormone produced and the age and sex of the host.14 Histologic examination of the tumor gives no clue to the type of hormone produced, if any. It is to be hoped that newer histochemical methods may improve this situation.15 When endocrine ef- fects are apparent, as Cahill has pointed out, they usually can be assessed as the effects of estrogens, androgens or corticoids (“11-oxyste- roids”) produced by the tumor .* The type of steroid present in excess may be determined by extraction of biologic fluids and chemical assay or bioassay in laboratory animals, or by clinical assessment of the effects of the hor- mone upon the patient, a “clinical bioassay.”
The appearance of gynecomastia in our patient provides an interesting example of *Recently, 2 cases of adrenal cortical tumors associated with the excretion of chorionic gonadotrophin have been reported, providing a further and still rarer classification.16, 17
specificity (or nonspecificity?) of steroidal in- fluence. Inasmuch as development of breasts is a feminine characteristic, gynecomastia has been regarded as evidence of “feminization.” It is only when one attempts to appraise this abnor- mality as a manifestation of known effects of steroidal hormones that the complexity of the problem becomes apparent. Production of mam- mary growth has been reported in a number of species-including man-by estrogens,18 andro- gens,19 and desoxycorticosterone.2º Nor does the histologic appearance of the breast aid greatly, for ductal, and particularly periductal, hyper- trophy may be induced by testosterone as well as by estrogens.21 It is therefore apparent that in this case the appearance of the breast pro- vided no specific information whether the steroid produced in excess was estrogenic or androgenic.
In the testis, however, a different situation exists. The persistence of spermatogenesis is in- consistent with the production of large amounts of an estrogenic steroid. On the other hand, it has been shown repeatedly, contrary to wide- spread misconceptions, that testosterone is a potent stimulator of spermatogenesis (vide infra). In this patient, from the appearance of the testis alone, one might suspect that the hor- mone produced was similar to testosterone and was not an estrogen. A number of other points strengthen this concept. The patient had main- tained normal libido, potency and shaving hab- its, in contrast to the syndrome observed in patients with estrogen-producing tumors of the adrenal cortex.22,23 The conclusion that the
steroid produced was similar to testosterone is further substantiated by the absence of cachexia despite multiple metastases, the lack of atrophy of the other adrenal, the absence of estrogenic metaplasia of the prostate, and the occurrence of polycythemia. This clinical impression is con- firmed by the very high urinary 17-ketosteroid level, a phenomenon which cannot be assigned to the production of excess estrogenic steroids, inasmuch as estrogens are not excreted as 17-ketosteroids.
T HE hypertension is more difficult to inter- pret, since the ischemic right kidney pro- vided a possible cause other than hormonal. It should be noted that the patient did not present the clinical appearance of Cushing’s disease: no buffalo-type obesity, thin skin, striae, osteoporosis or glycosuria, or the contralateral adrenal atrophy or testicular damage commonly associated with excess of 11-oxycorticosteroids.
The knowledge of the effects of excessive testosterone in the adult male has been derived from the experimental administration of large amounts of testosterone to men as well as from observation of patients in whom large amounts of androgen are produced by an interstitial cell tumor of the testis. It is of some interest to com- pare such effects with the findings in our case.
The administration of large amounts of tes- tosterone for long periods of time may produce many of the phenomena observed in this case.
Weight gain is a constant anabolic feature as- sociated with the administration of testosterone. Possibly this may explain why patients with numerous metastases from secreting tumors of the interstitial cells do not develop cachexia and have relatively long duration of life, as noted by Masson.24 This significant characteristic of testosterone may prove useful in the treatment of debilitating diseases from other causes.
The maintenance of spermatogenesis with tes- tosterone has been shown in the hypophysec- tomized rat by Walsh, Cuyler and McCullagh.25 Simpson and Evans26 not only confirmed the maintenance of spermatogenesis and normal mating behavior in hypophysectomized rats treated with testosterone but also their ability to sire a litter. A similar observation has been made in an hypogonadotrophic eunuchoid patient by Kinsell27 and in normal young men by Beller and Turner.28
Administration of testosterone to young boys29 occasionally leads to gynecomastia. The same effect may occur in old men and in eunuch- oids.30 As far as we know, the production of gynecomastia has not been reported in normal young adult men being treated with testosterone. We have, however, seen one patient, a 35 year old psychologist, who, following a course of psychoanalysis, felt unduly fatigued. This patient was treated elsewhere with 100 mg. of tes- tosterone propionate twice weekly for two and one-half years, during which time he developed gynecomastia.
It has been postulated by Klinefelter, Reifen- stein and Albright31 that testosterone directly stimulates mammary development but is nor- mally counterbalanced by a tubular secretion of the testis. This hypothesis would explain the occurrence of gynecomastia in young boys and old men as well as in eunuchoids treated with testosterone. Overdosage with testosterone in young adults might also produce gynecomastia if the amount were sufficient to overcome the hypothetical tubular secretion, as in the case of the psychologist already cited. As an alternative hypothesis, it might be postulated that the pro- duction of gynecomastia is not necessarily a direct effect, inasmuch as it has been shown that the administration of testosterone pro- pionate results in increased excretion of estro- gen in the urine.32
The induction of polycythemia with massive doses of testosterone propionate in patients with mammary carcinomatosis has been reported by Adair and others.33
Since the rise in 17-ketosteroid excretion in the urine after administration of testosterone propionate usually corresponds to about 40 per cent of the administered dose,34 the theoretical production of testosterone-like steroids in this patient, who excreted 225 mg. of urinary 17- ketosteroids daily, might exceed 500 mg. per day.
A careful survey of the literature dealing with adrenal cortical tumors discloses two other cases, one reported by Armstrong and Simpson35 and one by W. W. Scott,36 in which a syndrome
similar to that displayed by this patient was produced in an adult male by an adrenal corti- cal tumor. The case of Armstrong and Simpson was reported as an example of adrenal “fem- inism” because of the presence of gynecomastia. However, 17-ketosteroid excretion rose progres- sively to the fairly high level of 108 mg. per day, and there was no evidence of estrogeniza- tion of the testes. In their case the gynecomastia was associated not only with dilated ducts but also with “abundant glandular tissue producing a picture not unlike that of a female breast.” It is, therefore, possible that this may have been an example of mixed androgenic and estrogenic production. In this respect, their case is similar to that of Roholm and Teilum.37
The case of W.W. Scott, described in a paper by Lawson Wilkins as an example of a “fem- inizing tumor,” was that of a 43 year old man with gynecomastia, reduced libido and potency, normal hair and pigmentation, and abnormally high 17-ketosteroid excretion of 196 mg. per day. Analysis of the urinary steroids showed a large amount of dehydroisoandrosterone with no increase in estrogens. The case reported by Lisser23 in 1936, but autopsied in 1925, might have been another instance of gynecomastia in an adult male due to an androgenic tumor of the adrenal cortex, since it was specifically men- tioned that the luxuriant hirsutism of chest and abdomen had not been affected. Determinations of 17-ketosteroid excretion were not performed in 1925.
References cited in this article will be included in the authors’ reprints.