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Prepubertal male gynecomastia
February, 1972 The ]ourrml of P E D I A T R I C S
259
Prepubertal male gynecomastia Only 18 cases o[ prepubertal male gynecomastia are recorded in the medical literature; to these we add 5 more. The need to differentiate idiopathic gynecomastia [rom pathologically induced causes is discussed. The microscopic examination of the breast tissue in one of our patients showed cystic dilation of the ducts, a rarely described occurrence in prepubertal children.
Gilbert P. August, M.D.,* Roma Chandra, M.B., B.S., and Wellington Hung,
M.D., Washington, D. C.
breast e n l a r g e m e n t i n prepubertal females is a p h e n o m e n o n well k n o w n to pediatricians, little has been written about prepubertal breast e n l a r g e m e n t i n the male. U n t i l 1965, only 10 cases h a d been reported in the literature? I n the past 6 months we have seen two prepubertal males with breast enlargement. This has prompted us to reexamine its frequency, review the literature on this subject a n d survey the records of the pathology d e p a r t m e n t of the Children's Hospital since 1960 for additional cases. A L T H O U O K
CASE REPORTS Case 1. Patient H. B. was a 9~2-year-old boy in whom unilateral breast enlargement was first noted in the fall of 1969. There was no history From the Departments of Endocrinology and Pathology of the Children's Hospital of the District of Columbia, the Department of Pediatrics of George Washington University, and the Department of Pathology o[ Georgetown University. Supported in part by a grant (RR-284) [rom the General Clinical Research Centers Program of the Division of Research Resources, National Institutes o[ Health (G.P.A.). ~Reprint address: The Children's Hospital of the Distr~et o] Columbia,, 2125 13th St., N.W., Washington, D.C. 20009.
of pain, tenderness, or an increased growth rate. There was no known contact with estrogenic agents. Physical examination. Height was 128.5 cm. and weight was 25 Kg. The penis measured 4.5 x 1.5 cm. and was without evidence of androgenic stimulation. The testes measured 1.9 x 0.9 cm. bilaterally. Breast tissue was noted on the left measuring 3 x 3 cm. The areola was 18 mm. in diameter and was not pigmented. Laboratory data. Urinary excretion of 17-ketosteroids was less than 0.5 mg. per day; estrogens were 1 /~g per day (Bioscience Laboratories) and urinary gonadotropins were positive between 6 and 16 mouse uterine units per day. The T 4 was 6.3 /~g per cent. The karyotype was XY in peripheral lymphocytes. The bone age was 6 years. Breast tissue was surgically removed in November, 1970. Pathology. Sections showed mammary ducts in a fibrous stroma, encompassing lobules of adipose tissue. There was florid ductal proliferation associated with proliferation of the lining epithelium which was piled up and projected into the lumina of some of the ducts in the form of papillary projections. The periducta.1 stroma was generally loose and cellular, but in areas it Vol. 80, No. 2, pp. 259-263
260
August, Chandra, and Hung
The Journal of Pediatrics February 1972
Fig. 1. Case 2. Cystically dilated ducts in a collagenous stroma. (x50.)
was dense and merged with the interlobular collagenous stroma. Minimal mononuclear cell infiltrate was present in the loose periductal stroma. No acini were seen. Case 2. Patient S. A. was a 2f~-year-old boy who was first seen on December 15, 1970, with a history of a swelling in the left breast of two weeks' duration. There was no pain, tenderness, accelerated growth rate, or contact with estrogenic agents. Physical examination. Height was 88.5 cm. and weight was 10.5 Kg. The penis showed no signs of androgenic stimulation. Both testes were in the scrotum, were of prepubertal consistency, and were without nodules. The left upper quadrant of the left breast contained a soft, 1.5 x 3 cm. nodule. The areola was 10 ram. in diameter and was not pigmented. Examination of the exfoliated cells of the urogenital tract revealed 90 per cent basal cells and t0 per cent intermediate cells, thus demonstrating a lack of significant estrogenic stimulation. An excisional biopsy was performed on December 30, 1970. Pathology. Sections (Fig. 1) demonstrated mammary tissue consisting of dilated ducts which were lined by a single to two-layered epithelium and contained eosinophilic secretion. No epithelium proliferation was evident. In areas the ducts appeared increased in number without cystic dilation. The periductal stroma was densely collagenous and merged with the interlobular collagenous stroma. Focal aggregates of Iymphocytes were present in the stroma. No acinl were seen.
Records of the Children's Hospital of the
District o[ Columbia. Since 1960 the Pathology Department has received three other specimens of breast tissue from boys with prepubertal gynecomastia (Table I ) . DISCUSSION I n contradistinction to the female, idiop a t h i c p r e p u b e r t a l m a l e gynecomastia appears to be rare. T o the 18 cases r e p o r t e d in the literature, 1-1a we h a v e a d d e d 3 cases culled from the p a t h o l o g y records of the Children's H o s p i t a l of the District of Columbia a n d 2 cases seen by us. O f the 23 recorded cases, the breast e n l a r g e m e n t occurred 7 times on the left a n d 4 times on the right side. However, no m e n t i o n of location was m a d e in the m a j o r i t y of r e p o r t e d cases. Before a diagnosis of i d i o p a t h i c gynecomastia can be m a d e , one must consider all possible causes. G y n e c o m a s t i a has been associated not only with the a d m i n i s t r a t i o n of estrogens b u t also with o t h e r h o r m o n a l a n d n o n h o r m o n a l drugs. 14 A n exhaustive environm e n t a l a n d d r u g history should be t a k e n ; estrogens are included in some geriatric tonics. T h e relationship between excess estrogens a n d resultant breast d e v e l o p m e n t is well established. However, clinical experience seems to indicate t h a t gynecomastia is most often associated with conditions t h a t a r e not acc o m p a n i e d b y estrogen excess. G y n e c o m a s t i a can be i n d u c e d by androgens, either endog-
Volume 80 Number 2
Prepubertal male gynecomastia 2 6 1
Table I. Cases from Children's Hospital of the District of Columbia
Patient
t Age~ I Durati~ onset (yr.) (yr.)
T.W.
2~2
16A2
J.W.D
3
2
C.S.
9
~2
[
Size
Location
Pathology
Right
Gynecomastia; no ductal or epithelial proliferation; dense collagenous stroma
2 x 2 x 1 cm.
Right
Gynecomastia; ductal and epithelial proliferations; dense periductal stroma merging with collagenous interlobular stroma
1.5 x 1 x 0.2 cm.
Left
Gynecomastia; ductal and epithelial proliferation, generally dense periductal stroma merging with eollagenous and interlobular stroma
15 x 20 cm.
enously produced by interstitial cell tumors of the testes, 1~ by adrenal disorders, 16 or by exogenously administered androgensY Gynecomastia can also be associated with excessive concentrations of gonadotropins? s-2~ Although the majority of cases of gynecomastia in males of all ages is associated with a variety of seemingly unconnected nonendocrine diseases, 2, 7, 1~, 21, 22 the possibility of an endocrine tumor bears a prominent place in the diagnostic workup of these patients. Endocrine studies are indicated to rule out the rare feminizing adrenal tumor, interstitial cell tumors of the testes, and gonadotropin secreting tumors? s, 22 The feminizing adrenal tumor should be detected by elevated urinary excretion of 17-ketosteroids and estrogens. Interstitial cell tumors of the testes may be detected by abnormality in size of a testis or by a nodule in one of them, or by an elevation of the concentration of testosterone in the plasma or in the urine. Gonadotropinsecreting tumors may be detected by an elevated urinary excretion of either total gonadotropins or, specifically, chorionic gonadotropin. They may also be detected by an elevated serum concentration of luteinizing hormone with which chorionic gonadotropin is immunologically cross-reactive. Interstitial cell tumors of the testes should not be overlooked as a canse of gynecomastia in prepubertal males; 5 such cases have been reported. 15 One of the children seen by us (S. A.) had
extensive cystic dilatation of the ductal system, which we initially thought to be a rather unique type of lesion in a child. Cystic dilatation had been described in adult male gynecomastia, albeit uncommonly: 2/130 by Menville 3 and 5/284 by Karsner. 24 Dilated ducts were found in an additional 6 of Menville's 2 cases and in 63 of Karsner's. ~4 In an extensive study of the pathologic changes seen in the breast during childhood, Chumachenko 11 found 250 cases (131 in boys and 119 in girls) of pathologically discernible gynecomastia in children aged 6 months to 15 years who had died of various causes. I n 15 of these (9 boys and 6 girls) the changes were cystic dilatation. However, in only two were the cysts surgically removed; the remainder were incidental findings in children who had died suddenly. The cysts were found in 11 children under 2 ~ years of age, in 2 children aged 5, and in 2 aged 7 years. I n two series the duration of gynecomastia has beer/found to affect the pathologic appearance. The accumulation of fibrous connective tissue is associated with a longer duration of gynecomastiaY, 13 These changes are particularly marked after one year's duration. Study of the exfoliated cells of the urogenital tract, 25, 26 as an in vivo bioassay for estrogen, in girls with premature thelarche and in boys with adolescent gynecomastia, often shows a slightly increased estrogen effect. However, studies of the urinary excretion of estrogens 27 have failed to demon-
262
August, Chandra, and Hung
strate any increase. This led to the theory that premature thelarche, a n d by extension idiopathic prepubertal male gynecomastia, was due to an increased end-organ sensitivity to n o r m a l concentrations of circulating estrogens. However, in studies of girls with prem a t u r e thelarche, elevated m e a n concentrations of serum luteinizing h o r m o n e a n d follicle-stimulating h o r m o n e 28 have been found. Measurements of serum estradiol by radioimmunoassay have shown similar increases. 29 I t would not be necessary to demonstrate elevated concentrations of serum lu* teinizing hormone, follicle-stimulating hormone, or estradiol in all such children in order to explain the etiology of p r e m a t u r e thelarche u p o n increased circulating estrogens, for the biological effects of estrogen can r e m a i n long after the estrogen levels have r e t u r n e d to normal. A l t h o u g h we have concentrated our discussion on gynecomastia due to hypertrophy of the breast elements, it can also be due to tumorous changes. C a r c i n o m a of the breast in childhood is quite rare; only 33 cases were reported prior to 1958 a~ a n d an additional case was added in 1969. 31 Lipomas, neurofibromas, 32 a n d hemangiomas al are also to be considered.
The Journal o[ Pediatrics February 1972
8. 9.
10. Ii. 12. 13.
14. 15. 16. 17.
18. 19.
REFERENCES
1. Snoga, J. R., Morgan, R. L., and Lundberg, G. D.: Idiopathic prepubertal hypertrophy of the male breast, Am. J. Clin. Pathol. 44: 458, 1965. 2. Ingleby, H.: Two cases of so-called gynaecomastia in young boys, Br. Med. J. 2: 631, 1919. 3. Menville, J. G.: Gynecomastia, Arch. Surg. 26" 1054, 1933. 4. Schnurbusch, F.: Untersuchunger Uber die Morphologie der mgnnlichen Brustdriise w~ihrend des Ledensablaufes als Grundlage fur eln Studium der Gyn~ikomastie, Frankfort Z. Pathol. 62: 402, 1951. 5. Grinberg, R., Jaroslavsky, L., Stutman, G., and Schaplra, R.: Ginecomastia en un nifio de once afios; estudio y tratamieto, Prensa M~d. argent. 40: 2828, 1953. 6. Haagensen, C. D.: Diseases of the breast, Philadelphia, 1956, W. B. Saunders Company, p. 71. 7. Treves, N.: Gynecomastia; the origins of mammary swelling in the male. An analysis of 406 patients with breast hypertrophy, 525 with
20. 21. 92. 23. 24. 25.
26. 27.
testicular tumors, and 13 with adrenal neoplasms, Cancer t1: 1083, 1958. Jull, J. W., Bonser, G. M., and Dossett, J. A.: Hormone excretion studies of males with gynecomastia, Br. Med. J. 2: 797, 1964. Dreseh, C., Arnal, M., and Prader, A,: Etude de 22 Cas de D6veloppement Pr6matur6 Isol6 des Seins ou "Premature Thelarche," Helv. Pediatr. Acta 15: 585, 1960. Walezak, M., Wojciechowski, K., Bartkowiak, Z., and Pawlaczyk, J.: Treatment of gynecomastia in boys, Pediatr. Pol. 45: 1041, 1970. Chumachenko, P. A.: On the problem of pathological changes of the human breast in childhood, Arkh. Fatol. 30: 56, 1968. James, T.: Familial unilateral gynaecomastia in an adolescent, S. Aft. Med. J. 31: 781, 1957. Nieolls, G. L., Modlinger, R. S., and Gabrilove; J. L.: A study of the histopathology of human gynecomastia, J. Clln. Endocrinol. Metab. 32: 173, 1971. Editorial: Gynecomastia, Lancet 2: 1548, 1964. Johnstone, G.: Prepubertal gynaecomastia in association with an interstitial cell tumour of the testes, Br. J. UroI. 39: 211, i967. Marchandise, B., and Lederer, J.: Gyn6comastia par Exc&s de Dihydro-6piandrosterone, Rev. Franc. Endocrinol. Clin. 7: 383, 1966. McCullagh, E. P., and Rossmiller, H. R.: Methyltestosterone. I. Androgenic effects and the production of gynecomastia and oligospermia, J. Clin. Endocrinol. Metab. 1: 496, 1941. Rudnick, P., and Odell, W. D.: In search of a cancer, N. Engl. J. Med. 284: 405, 1971. Klinefelter, H. F., Reifenstein, F. C., and Albright, F.: Syndrome characterized by gynecomastia, aspermatogenesis without A-leydigism, and increased excretion of folliclestimulating hormone, J. Clin. Endocrinol. Metab. 2: 615, 1942. Heller, C. G., Nelson, W. O., and Roth, A. A.: Functional prepubertal castration in males, J. Clin. Endocrinol. Metab. 3: 573, 1943. Keddie, N., and Morris, P. J.: Male breast tumors, Surg. Gynecol. Obstet. 124: 332, 1967. Dexter, C. J.: Benign enlargement of the male breast, N. Engl. J. Med. 254: 996, 1956. August, G. P.: Diagnosis of disorders of sexual maturation, Pediatr. Clin. North. Am. 18: 313, 1971. Karsner, H. T.: Gynecomastia, Am, J. Pathol. 22: 235, 1946. Collett-Solberg, P. R., and Grumbach, M. M.: A simplified procedure for evaluating estrogenic effects and the sex chromatin pattern in exfoliated cells in urine: Studies in premature thelarche and gynecomastia of adolescence, J. PEDIATm 66: 883, 1965. Preeyasombat, C., and Kenny, F. M.: Urocytogram in normal children and various abnormal conditions, Pediatrics 38: 436, 1966. Jull, J. W., and Dossett, J. A.: Hormone ex-
Volume 80 Number 2
cretion studies of gynaecomastia of puberty, Br. Med. J. 2" 795, 1964. 28. Kenny, F. M., Midgley, A. R., Jaffe, R. B., Garces, L. Y., Vasquez, A., and Taylor, F. It.: Radioimmunoassayable serum LH and FSH in girls with sexual precocity, premature thelarche, and adrenarche, J. Clin. Endocrinol. Metab. 29: 1272, 1969. 29. Jenner, M. R., Kelch, R. P., Kaplan, S. L., and Grumbach, M. M.: Plasma estradiol in prepubertal children, pubertal females, and in precocious puberty, premature thelarche, and in feminizing ovarian tumor. Abstract, Am. Pediatr. Soe., Atlantic City, N. J., 1971, p. 5.
Prepubertal male gynecomastia
2 63
30. Herrman, J. B.: In Ariel, I. M., and Pacl% G. T., editors: Cancer and allied diseases of infancy and childhood, Boston, 1960, Little, Brown & Company. 31. Simpson, J. S., and Barson, A. J,: Breast tumours in infants and children: A 40-year review of cases at a children's hospital, Can. Med. Assoc. J. 101: I00, 1969. 32. Fienman, N. L., and Yakovac, W. C.: Neurofibromatosis in childhood, J. PEDIATR.76: 339, 1970.
259
Prepubertal male gynecomastia Only 18 cases o[ prepubertal male gynecomastia are recorded in the medical literature; to these we add 5 more. The need to differentiate idiopathic gynecomastia [rom pathologically induced causes is discussed. The microscopic examination of the breast tissue in one of our patients showed cystic dilation of the ducts, a rarely described occurrence in prepubertal children.
Gilbert P. August, M.D.,* Roma Chandra, M.B., B.S., and Wellington Hung,
M.D., Washington, D. C.
breast e n l a r g e m e n t i n prepubertal females is a p h e n o m e n o n well k n o w n to pediatricians, little has been written about prepubertal breast e n l a r g e m e n t i n the male. U n t i l 1965, only 10 cases h a d been reported in the literature? I n the past 6 months we have seen two prepubertal males with breast enlargement. This has prompted us to reexamine its frequency, review the literature on this subject a n d survey the records of the pathology d e p a r t m e n t of the Children's Hospital since 1960 for additional cases. A L T H O U O K
CASE REPORTS Case 1. Patient H. B. was a 9~2-year-old boy in whom unilateral breast enlargement was first noted in the fall of 1969. There was no history From the Departments of Endocrinology and Pathology of the Children's Hospital of the District of Columbia, the Department of Pediatrics of George Washington University, and the Department of Pathology o[ Georgetown University. Supported in part by a grant (RR-284) [rom the General Clinical Research Centers Program of the Division of Research Resources, National Institutes o[ Health (G.P.A.). ~Reprint address: The Children's Hospital of the Distr~et o] Columbia,, 2125 13th St., N.W., Washington, D.C. 20009.
of pain, tenderness, or an increased growth rate. There was no known contact with estrogenic agents. Physical examination. Height was 128.5 cm. and weight was 25 Kg. The penis measured 4.5 x 1.5 cm. and was without evidence of androgenic stimulation. The testes measured 1.9 x 0.9 cm. bilaterally. Breast tissue was noted on the left measuring 3 x 3 cm. The areola was 18 mm. in diameter and was not pigmented. Laboratory data. Urinary excretion of 17-ketosteroids was less than 0.5 mg. per day; estrogens were 1 /~g per day (Bioscience Laboratories) and urinary gonadotropins were positive between 6 and 16 mouse uterine units per day. The T 4 was 6.3 /~g per cent. The karyotype was XY in peripheral lymphocytes. The bone age was 6 years. Breast tissue was surgically removed in November, 1970. Pathology. Sections showed mammary ducts in a fibrous stroma, encompassing lobules of adipose tissue. There was florid ductal proliferation associated with proliferation of the lining epithelium which was piled up and projected into the lumina of some of the ducts in the form of papillary projections. The periducta.1 stroma was generally loose and cellular, but in areas it Vol. 80, No. 2, pp. 259-263
260
August, Chandra, and Hung
The Journal of Pediatrics February 1972
Fig. 1. Case 2. Cystically dilated ducts in a collagenous stroma. (x50.)
was dense and merged with the interlobular collagenous stroma. Minimal mononuclear cell infiltrate was present in the loose periductal stroma. No acini were seen. Case 2. Patient S. A. was a 2f~-year-old boy who was first seen on December 15, 1970, with a history of a swelling in the left breast of two weeks' duration. There was no pain, tenderness, accelerated growth rate, or contact with estrogenic agents. Physical examination. Height was 88.5 cm. and weight was 10.5 Kg. The penis showed no signs of androgenic stimulation. Both testes were in the scrotum, were of prepubertal consistency, and were without nodules. The left upper quadrant of the left breast contained a soft, 1.5 x 3 cm. nodule. The areola was 10 ram. in diameter and was not pigmented. Examination of the exfoliated cells of the urogenital tract revealed 90 per cent basal cells and t0 per cent intermediate cells, thus demonstrating a lack of significant estrogenic stimulation. An excisional biopsy was performed on December 30, 1970. Pathology. Sections (Fig. 1) demonstrated mammary tissue consisting of dilated ducts which were lined by a single to two-layered epithelium and contained eosinophilic secretion. No epithelium proliferation was evident. In areas the ducts appeared increased in number without cystic dilation. The periductal stroma was densely collagenous and merged with the interlobular collagenous stroma. Focal aggregates of Iymphocytes were present in the stroma. No acinl were seen.
Records of the Children's Hospital of the
District o[ Columbia. Since 1960 the Pathology Department has received three other specimens of breast tissue from boys with prepubertal gynecomastia (Table I ) . DISCUSSION I n contradistinction to the female, idiop a t h i c p r e p u b e r t a l m a l e gynecomastia appears to be rare. T o the 18 cases r e p o r t e d in the literature, 1-1a we h a v e a d d e d 3 cases culled from the p a t h o l o g y records of the Children's H o s p i t a l of the District of Columbia a n d 2 cases seen by us. O f the 23 recorded cases, the breast e n l a r g e m e n t occurred 7 times on the left a n d 4 times on the right side. However, no m e n t i o n of location was m a d e in the m a j o r i t y of r e p o r t e d cases. Before a diagnosis of i d i o p a t h i c gynecomastia can be m a d e , one must consider all possible causes. G y n e c o m a s t i a has been associated not only with the a d m i n i s t r a t i o n of estrogens b u t also with o t h e r h o r m o n a l a n d n o n h o r m o n a l drugs. 14 A n exhaustive environm e n t a l a n d d r u g history should be t a k e n ; estrogens are included in some geriatric tonics. T h e relationship between excess estrogens a n d resultant breast d e v e l o p m e n t is well established. However, clinical experience seems to indicate t h a t gynecomastia is most often associated with conditions t h a t a r e not acc o m p a n i e d b y estrogen excess. G y n e c o m a s t i a can be i n d u c e d by androgens, either endog-
Volume 80 Number 2
Prepubertal male gynecomastia 2 6 1
Table I. Cases from Children's Hospital of the District of Columbia
Patient
t Age~ I Durati~ onset (yr.) (yr.)
T.W.
2~2
16A2
J.W.D
3
2
C.S.
9
~2
[
Size
Location
Pathology
Right
Gynecomastia; no ductal or epithelial proliferation; dense collagenous stroma
2 x 2 x 1 cm.
Right
Gynecomastia; ductal and epithelial proliferations; dense periductal stroma merging with collagenous interlobular stroma
1.5 x 1 x 0.2 cm.
Left
Gynecomastia; ductal and epithelial proliferation, generally dense periductal stroma merging with eollagenous and interlobular stroma
15 x 20 cm.
enously produced by interstitial cell tumors of the testes, 1~ by adrenal disorders, 16 or by exogenously administered androgensY Gynecomastia can also be associated with excessive concentrations of gonadotropins? s-2~ Although the majority of cases of gynecomastia in males of all ages is associated with a variety of seemingly unconnected nonendocrine diseases, 2, 7, 1~, 21, 22 the possibility of an endocrine tumor bears a prominent place in the diagnostic workup of these patients. Endocrine studies are indicated to rule out the rare feminizing adrenal tumor, interstitial cell tumors of the testes, and gonadotropin secreting tumors? s, 22 The feminizing adrenal tumor should be detected by elevated urinary excretion of 17-ketosteroids and estrogens. Interstitial cell tumors of the testes may be detected by abnormality in size of a testis or by a nodule in one of them, or by an elevation of the concentration of testosterone in the plasma or in the urine. Gonadotropinsecreting tumors may be detected by an elevated urinary excretion of either total gonadotropins or, specifically, chorionic gonadotropin. They may also be detected by an elevated serum concentration of luteinizing hormone with which chorionic gonadotropin is immunologically cross-reactive. Interstitial cell tumors of the testes should not be overlooked as a canse of gynecomastia in prepubertal males; 5 such cases have been reported. 15 One of the children seen by us (S. A.) had
extensive cystic dilatation of the ductal system, which we initially thought to be a rather unique type of lesion in a child. Cystic dilatation had been described in adult male gynecomastia, albeit uncommonly: 2/130 by Menville 3 and 5/284 by Karsner. 24 Dilated ducts were found in an additional 6 of Menville's 2 cases and in 63 of Karsner's. ~4 In an extensive study of the pathologic changes seen in the breast during childhood, Chumachenko 11 found 250 cases (131 in boys and 119 in girls) of pathologically discernible gynecomastia in children aged 6 months to 15 years who had died of various causes. I n 15 of these (9 boys and 6 girls) the changes were cystic dilatation. However, in only two were the cysts surgically removed; the remainder were incidental findings in children who had died suddenly. The cysts were found in 11 children under 2 ~ years of age, in 2 children aged 5, and in 2 aged 7 years. I n two series the duration of gynecomastia has beer/found to affect the pathologic appearance. The accumulation of fibrous connective tissue is associated with a longer duration of gynecomastiaY, 13 These changes are particularly marked after one year's duration. Study of the exfoliated cells of the urogenital tract, 25, 26 as an in vivo bioassay for estrogen, in girls with premature thelarche and in boys with adolescent gynecomastia, often shows a slightly increased estrogen effect. However, studies of the urinary excretion of estrogens 27 have failed to demon-
262
August, Chandra, and Hung
strate any increase. This led to the theory that premature thelarche, a n d by extension idiopathic prepubertal male gynecomastia, was due to an increased end-organ sensitivity to n o r m a l concentrations of circulating estrogens. However, in studies of girls with prem a t u r e thelarche, elevated m e a n concentrations of serum luteinizing h o r m o n e a n d follicle-stimulating h o r m o n e 28 have been found. Measurements of serum estradiol by radioimmunoassay have shown similar increases. 29 I t would not be necessary to demonstrate elevated concentrations of serum lu* teinizing hormone, follicle-stimulating hormone, or estradiol in all such children in order to explain the etiology of p r e m a t u r e thelarche u p o n increased circulating estrogens, for the biological effects of estrogen can r e m a i n long after the estrogen levels have r e t u r n e d to normal. A l t h o u g h we have concentrated our discussion on gynecomastia due to hypertrophy of the breast elements, it can also be due to tumorous changes. C a r c i n o m a of the breast in childhood is quite rare; only 33 cases were reported prior to 1958 a~ a n d an additional case was added in 1969. 31 Lipomas, neurofibromas, 32 a n d hemangiomas al are also to be considered.
The Journal o[ Pediatrics February 1972
8. 9.
10. Ii. 12. 13.
14. 15. 16. 17.
18. 19.
REFERENCES
1. Snoga, J. R., Morgan, R. L., and Lundberg, G. D.: Idiopathic prepubertal hypertrophy of the male breast, Am. J. Clin. Pathol. 44: 458, 1965. 2. Ingleby, H.: Two cases of so-called gynaecomastia in young boys, Br. Med. J. 2: 631, 1919. 3. Menville, J. G.: Gynecomastia, Arch. Surg. 26" 1054, 1933. 4. Schnurbusch, F.: Untersuchunger Uber die Morphologie der mgnnlichen Brustdriise w~ihrend des Ledensablaufes als Grundlage fur eln Studium der Gyn~ikomastie, Frankfort Z. Pathol. 62: 402, 1951. 5. Grinberg, R., Jaroslavsky, L., Stutman, G., and Schaplra, R.: Ginecomastia en un nifio de once afios; estudio y tratamieto, Prensa M~d. argent. 40: 2828, 1953. 6. Haagensen, C. D.: Diseases of the breast, Philadelphia, 1956, W. B. Saunders Company, p. 71. 7. Treves, N.: Gynecomastia; the origins of mammary swelling in the male. An analysis of 406 patients with breast hypertrophy, 525 with
20. 21. 92. 23. 24. 25.
26. 27.
testicular tumors, and 13 with adrenal neoplasms, Cancer t1: 1083, 1958. Jull, J. W., Bonser, G. M., and Dossett, J. A.: Hormone excretion studies of males with gynecomastia, Br. Med. J. 2: 797, 1964. Dreseh, C., Arnal, M., and Prader, A,: Etude de 22 Cas de D6veloppement Pr6matur6 Isol6 des Seins ou "Premature Thelarche," Helv. Pediatr. Acta 15: 585, 1960. Walezak, M., Wojciechowski, K., Bartkowiak, Z., and Pawlaczyk, J.: Treatment of gynecomastia in boys, Pediatr. Pol. 45: 1041, 1970. Chumachenko, P. A.: On the problem of pathological changes of the human breast in childhood, Arkh. Fatol. 30: 56, 1968. James, T.: Familial unilateral gynaecomastia in an adolescent, S. Aft. Med. J. 31: 781, 1957. Nieolls, G. L., Modlinger, R. S., and Gabrilove; J. L.: A study of the histopathology of human gynecomastia, J. Clln. Endocrinol. Metab. 32: 173, 1971. Editorial: Gynecomastia, Lancet 2: 1548, 1964. Johnstone, G.: Prepubertal gynaecomastia in association with an interstitial cell tumour of the testes, Br. J. UroI. 39: 211, i967. Marchandise, B., and Lederer, J.: Gyn6comastia par Exc&s de Dihydro-6piandrosterone, Rev. Franc. Endocrinol. Clin. 7: 383, 1966. McCullagh, E. P., and Rossmiller, H. R.: Methyltestosterone. I. Androgenic effects and the production of gynecomastia and oligospermia, J. Clin. Endocrinol. Metab. 1: 496, 1941. Rudnick, P., and Odell, W. D.: In search of a cancer, N. Engl. J. Med. 284: 405, 1971. Klinefelter, H. F., Reifenstein, F. C., and Albright, F.: Syndrome characterized by gynecomastia, aspermatogenesis without A-leydigism, and increased excretion of folliclestimulating hormone, J. Clin. Endocrinol. Metab. 2: 615, 1942. Heller, C. G., Nelson, W. O., and Roth, A. A.: Functional prepubertal castration in males, J. Clin. Endocrinol. Metab. 3: 573, 1943. Keddie, N., and Morris, P. J.: Male breast tumors, Surg. Gynecol. Obstet. 124: 332, 1967. Dexter, C. J.: Benign enlargement of the male breast, N. Engl. J. Med. 254: 996, 1956. August, G. P.: Diagnosis of disorders of sexual maturation, Pediatr. Clin. North. Am. 18: 313, 1971. Karsner, H. T.: Gynecomastia, Am, J. Pathol. 22: 235, 1946. Collett-Solberg, P. R., and Grumbach, M. M.: A simplified procedure for evaluating estrogenic effects and the sex chromatin pattern in exfoliated cells in urine: Studies in premature thelarche and gynecomastia of adolescence, J. PEDIATm 66: 883, 1965. Preeyasombat, C., and Kenny, F. M.: Urocytogram in normal children and various abnormal conditions, Pediatrics 38: 436, 1966. Jull, J. W., and Dossett, J. A.: Hormone ex-
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cretion studies of gynaecomastia of puberty, Br. Med. J. 2" 795, 1964. 28. Kenny, F. M., Midgley, A. R., Jaffe, R. B., Garces, L. Y., Vasquez, A., and Taylor, F. It.: Radioimmunoassayable serum LH and FSH in girls with sexual precocity, premature thelarche, and adrenarche, J. Clin. Endocrinol. Metab. 29: 1272, 1969. 29. Jenner, M. R., Kelch, R. P., Kaplan, S. L., and Grumbach, M. M.: Plasma estradiol in prepubertal children, pubertal females, and in precocious puberty, premature thelarche, and in feminizing ovarian tumor. Abstract, Am. Pediatr. Soe., Atlantic City, N. J., 1971, p. 5.
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30. Herrman, J. B.: In Ariel, I. M., and Pacl% G. T., editors: Cancer and allied diseases of infancy and childhood, Boston, 1960, Little, Brown & Company. 31. Simpson, J. S., and Barson, A. J,: Breast tumours in infants and children: A 40-year review of cases at a children's hospital, Can. Med. Assoc. J. 101: I00, 1969. 32. Fienman, N. L., and Yakovac, W. C.: Neurofibromatosis in childhood, J. PEDIATR.76: 339, 1970.