HORMONE THERAPY OF MALE BREAST HYPERTROPHY

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1 HORMONE THERAPY OF MALE BREAST HYPERTROPHY WILLIAM J. HOFFMAN, M.D. (From the Skin and Cancer Unit of brew York Post-Gradmte Hospital, Carl Eggers, Attending Surgeon) Hypertrophy of the male breast may occur at any age. It is of comparatively frequent occurrence in puberty and adolescence. The condition presents as a mass of breast tissue beneath the nipple and areola, usually measuring from 1 to 6 cm. in diameter, though larger masses are sometimes seen. Tenderness is a common finding and often is the first sign leading to the discovery of the condition. The lesion is benign and does not in itself predispose to cancer. Its clinical significance lies, nevertheless, in its relation to such tumors since, theoretically at least, cancer of the breast, when it occurs at a later period in the life of the male, selects those for its victims in whom active breast tissue is already present. The lesion is often subjected to surgery as a prophylactic against the possible development of malignant disease. In adolescent boys the majority of these masses undergo spontaneous regression, only one out of seven persisting after twenty years of age. Jung and Shafton, after a study of 1,000 supposedly normal males of all ages, found that the enlargement reached a maximum at the age of.25 years, and that slow changes in the subareolar mass continued for a long time, mostly in the direction of softening and complete disappearance, but sometimes in the direction of persistent, soft, glandular masses or various degrees of gynecomastia. These findings have been corroborated by other writers. The following evidence suggests that this unusual activity of mammary tissue represents a disturbance of the hormonal government of the breast: (1) the high incidence during puberty and adolescence or late in life at the age of sexual decline; (2) the disappearance of the majority of the masses of breast tissue by the time adulthood is reached; (3) the fact that the hypertrophy may accompany malignant tumors of the testicle, testicular atrophy, or castration. In view of the possibility that the condition might be due to a deficiency of the male sex hormone, the writer, in 1935, treated a group of six patients by injections of the anterior pituitary-like hormone (follutein, Squibb). Injections were given at weekly intervals over periods ranging from two to ten. No consistent results were obtained, and the experiment was abandoned after one year. In 1937 a clinical experiment was begun to determine the effect of injections of male sex hormone into boys and men with hypertrophy of the breast. Testosterone acetate and testosterone propionate (perandren, Ciba) were the preparations employed. The group of patients consisted of thirtyone males with unilateral or bilateral involvement. Age Distribution: The youngest patient in this group was eleven years of 1 Jung, F. T., and Shafton, A. L.: Illinois M. J. 73: 115,

2 248 WILLIAM J. HOFFMAN TABLE I : Results of Testosterone Treatment of Hypertrophy of the Male Breast Breast Size Case Age Condition in cm. Treat nient Result K.J. W.M. T.H. P.T. B.C. W.S. M.L. W.B. G.K. S.S. F.H. P.K. M.W. E.B. 15 6X6X3 30 8X6X2 15 Undescended right testicle Right testicle undescended x2 x2 3X3X1, 2X2X1 1XlX1 2X2X1 lxlxl Testosterone: 33 injections 12 injections 33 inject ions 12 injections injections 10 injections 75 per cent regression in 5 Regressed to 2 cm. in three Complete regression in 4 Complete regression in 5 Testicle did not descend Regressed to 2 cm. in six weeks. Complete regression in 4. Three later recurrence, 2 cm. in diameter, disappearing after 2 weeks of injections Regressed to 1 cm. in 6 weeks. Testicle did not descend. Patient did not return Complete regression in 5 Regressed to 2 cm. in 2. Regressed to 1 cm. in 2. Regressed to 2 cm. in 5 weeks. Complete regression in 33 Spontaneous regression in 8 Complete regression in 8 age; the oldest was a man of seventy-three years. Thirteen cases occurred between the ages of ten and fourteen years; six between the ages of fifteen and nineteen years; two between the ages of twenty and twenty-four years; two between twenty-five and twenty-nine years; two in the fourth decade, and one each in the fifth, seventh, and eighth decades. Nineteen of the twenty-eight patients were below the age of sixteen years. Size of the Mass of Breast Tissue: The masses of breast tissue varied in size from that of a fully developed breast of small female type, measuring 8,X 6 X 6 cm., to a barely palpable nodule 1 cm. in diameter. As would be elrpected, the larger masses were found in the older patients. Hormone Analyses: Because of lack of funds, adequate hormone studies could not be made on these patients. Tests for prolan and estrin were made on the urine in 7 cases, of which 3 gave a positive reaction for prolan. None gave a positive reaction for estrin. Treatment: Twenty-eight of these 3 1 patients, with various degrees of hypertrophy, received injections of testosterone, acetate or propionate (perandren, Ciba) twice a week. The remaining 3 patients, who were the youngest in the group, with the smallest masses of breast tissue and a history of beginning regression, were excluded from the experiment.

3 MALE BREAST HYPERTROPHY TABLE I :-Continued Case - E.Q. L.H. M.R. P.A. D.S. A.T. J.D. G.R. T.C. J.S. D.G. R.B. P.L..J.G. Age Condition ; urinary prolan positive; estrin negative Urinary prolan positive Urinary prolan positive Breast Size in cm. 6X6X6 5 x 5 x5 5 x 5 x5 3 X3.5 X2 2.5 X2.5 X2 2 x2 x2 1 x1 x1 6X4X2 8X6X4 Treat ment Anterior pituitary hormone injections for 10 ; testosterone injections for one year Testosterone : 180 injections in twenty-two 6 injections 32 injections 41 injections injections Result Breast grew to 8X8X6 cm. Boy grew 3 inches; gained 21 Ib.; genitalia became normal for age, 15 years Coniplete regression in 5. Marked increase in size of penis and in pubic hair Increased at first; then de-. creased ; now measures 3 X 2 X 2 cm. Complete regression in 3 90 per cent regression in 3 weeks. Complete regression in 10 weeks Complete regression in 4 Complete regression in 2 Complete regression in 2 Spontaneous regression in 2 Regressed to 1.5 cm. in 3 Regressed to 2 cm. in 3. Similar mass developed in right breast, but disappeared after injections in. 2 Complete regression in 3 Complete regression in 10 weeks The dosage employed in the first 6 patients was 5 mg. of testosterone acetate injected twice a week. After six the dosage in subsequent cases was increased to 25 mg. twice a week, when it became evident that the smaller dosage produced no testicular damage or arrest of the normal changes of puberty. RESULTS Among the 28 patients who received injections of testosterone, there were instances of complete regression of the mass, while in 9 cases the degree of regression exceeded 75 per cent. Some of the patients in this latter group stopped coming to the clinic for injections when they could no longer feel the mass. These cases are listed here as partial regressions because on the occasion of the last clinic visit, a nodule was recorded as still present, measuring from 1 to 2 cm. in diameter. The elapsed time before complete regression occurred varied from two to five, and the number of injections averaged 28 during an average treatment period of fourteen weeks. In general, the response was relatively

4 250 WILLIAM J. HOFFMAN rapid in the beginning. It was not unusual to note a regression of 50 per cent during the first four weeks. After the mass had been reduced to a diameter of 1 or 2 cm. the rate of regression was much slower. Sometimes this persistent residual nodule would remain unaffected for many weeks. Then, if all injections were stopped, it might disappear within a month. Undescended Testicles: There were two instances of undescended testicle in the series. In one case there was complete regression of the breast mass; in the other it was reduced to 1 cm., when the patient discontinued clinic visits. In neither of these two cases did the undescended testicle change its position. Failures: There was a complete failure to reduce the size of the breast mass in 2 cases. In both instances the breast increased in size despite treatment over a long period. One of these patients was a boy of thirteen years when he first applied to the clinic. His left breast was normal. His right breast measured 6 cm. in all diameters tind resembled a small female breast. He was below the average height and weight for his age, and his genital development was that of a nine-year old boy. Injections of the anterior pituitarylike hormone from pregnancy urine failed to affect the size of the breast or his general development, which remained stationary for more than a year. He was then given injections of testosterone propionate twice a week for ten. During this time the breast actually increased in size to 8 X 8 X 6 cm. Other changes occurred. His height increased three inches; his weight increased 21 pounds; and his genital development became normal for his age of fifteen years. In the second case in which testosterone injections failed to have any beneficial effect, the breast mass increased from 2 cm. in diameter to 4 cm. After more than a year it slowly shrank to a diameter of 3 cm. Recurrences: The follow-up of these patients has been difficult. Most of the patients are schoolboys and clinic visits interrupt their class attendance. Consequently, as soon as their breasts had regressed to normal they were reluctant to return for check-up examinations. In at least two instances there was a recurrence of the condition, which, however, responded to a second course of treatment. One other patient developed a mass in the opposite breast while the first mass was regressing. This second mass regressed two later, after a series of injections. DISCUSSION From any experiment conducted as empirically as this one, it is difficult to draw specific conclusions. A condition such as hypertrophy of the male breast, which is known frequently to undergo spontaneous regression, does not lend itself to easy evaluation of any therapeutic agent. From the observation of these patients during the past four years, and especially in the past two years, since the male hormone has been available for their experimental treatment, it appears that regression of the larger masses in the older group is swifter and more consistent than would have been expected in a similar untreated group. I believe that this experiment, empirical as it is, indicates that the r61e of the male sex hormone in the government of the male breast should receive further study.

5 MALE BREAST HYPERTROPHY 25 1 CONCLUSION Injections of testosterone propionate and testosterone acetate (perandren, Ciba) into 28 patients with hypertrophy of the male breast, were followed by complete regression in 12 cases and a reduction of more than 75 per cent in 9 others. There was complete failure in 2 cases. Spontaneous regression occurred in 3 untreated patients. In several instances were was evidence of stimulation of the developmental changes of puberty, as shown by increase in size of the penis, increase in the amount of pubic hair, and increased weight and height. In no case was there any gross evidence of testicular damage or arrest of the growth changes of puberty.