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Gynecomastia with congenital virilizing adrenal hyperplasia (11-β-hydroxylase deficiency)
Volume 86 Number 4
strophy of urinary bladder and concomitant malformations; a report based on 82 cases, Pediatrics 23:927, 1959. 17. Greenwood RD, Rosenthal A, Parisi L, Fyler DC, and Nadas AS: Extrffcardiac anomalies in infants with congenital heart disease, Pediatrics (in press). 18. Berdon WE, Hochberg B, Baker DH, Grossman H, and Santulli TV: The association of lumbo-sacral spine and genitourinary anomalies with imperforate anus, A m J Roentgenol 98:181, 1966. 19. Weber FM, Dooley RR, and Sparkes RS: Anal atresia, eye anomalies and an additional small abnormal acrorentcic chromosome (47, XX, Mar +): Report of a case, J PEDIATR76:594, 1970.
Gynecomastia with congenital viril&ing adrenal hyperplasia (11-[3hydroxylase deficiency) Noel K. Maelaren, M.D., Claude J. Migeon, M.D.,
Brief clinical and laboratory observations
579
20.
Kaufman RL, Quintan B, and Ternberg JL: Imperforate anus, vertebral anomalies and preaxial limb abnormalities, Birth Defects 8:85, 1972. 21. Freedom RM, and Gerald PS: Congenital cardiac disease and the Cat Eye syndrome, Am J Dis Child 126:}6, t973. 22. Dupont B, Dupont A, Bliddal J, Hoist E, Melchior JC, and Ottesen OE: Idiopathic hypercalcaemia of infancy. The Elfin face syndrome. Danish Med Bull 17:33, 1970. 23. Tandon R, and Edwards JE: Cardiac malformations associated with Down's Syndrome, Circulation 47:t349, 1973. 24. Welch RG: The Potter syndrome of renal agenesis, Br Med I 1:1102, 1958.
tion (12.7 gm/dl) and normal serum and blood concentrations of urea nitrogen 12 mg/dl, calcium 9.8 mg/dl, phosphorus 6.2 rag/all, sodium 136 mEq/1, potassium 4.9 mEq/1, and alkaline phosphatase 4.5 King-Armstrong units. Serum thyroxine concentration was normal (6.0/zg/dl by Murphy-Pattee method). Skeletal age at the left wrist was 2 years, 8 months (Greulich and Pyle). Skull rOentgenogram was normal. Normal renal outlines with no displacement of the kidneys 3 were noted in an intravenous pyelogram.
and Salvatore Raiti, M.D., Baltimore, Md.
GYNECOMASTIA h a s n o t b e e n d e s c r i b e d in association w i t h u n t r e a t e d c o n g e n i t a l a d r e n a l h y p e r p l a s i a . 1~2 This report deals with a 1-year-old boy who was t h o u g h t initially to h a v e a n a d r e n a l t u m o r , b u t in w h o m a 1 1 - f l - h y d r o x y l a s e d e f i c i e n c y was identified. C A S E REPORT Patient P. M., a 1-year-old black boy presented at the University of Maryland Hospital with unilateral breast enlargement of five month's duration. His general health had been excellent. He was the only child of unrelated black parents in their early twenties. The boy was muscular. Height was 85.5 cm and weight was 13.4 kg (height and weight age for 2 years). He had four teeth. His blood pressure was consistently elevated and ranged from 115/80 to 125/90. Breast tissue was palpable on the left side (3 x 3 cm) but not on the right(Fig. 1). The left areola was enlarged, pointed, and measured 1.7 cm in diameter compared to 1.3 cm on the right side. There was no acne or facial, axillary, or pubic hair. The penis was enlarged with a diameter of 2.5 cm and a stretched length of 6.5 cm. The testes were not enlarged and measured 1.3 x 1.0 cm bilaterally. He had normal fundi and no cushingoid features or organomegaly. The rest of the physical examination was normal. Laboratory data included a normal hemoglobin concentra-
From the Departments of Pediatrics of the University of Maryland School of Medicine and of The Johns Hopkins Hospital
Abbreviations used IVP: intravenous pyelogram 17KS: 17-ketosteroids 17OHCS: 17-hydroxycorticoids DHEA: dehydroepiandrosterone hFSH: serum follicle-stimulating hormone hLH: serum luteinizing hormone Urinary steroids were measured by the following methods: 17-ketosteroids by a modification of the method of Callow and associates 4 17-hydroxycorticoids by modification of the GlennNelson method and pregnanetriol by modification of the technique of Bongiovanni and Eberlein. 6 Baseline concentrations of 24-hour urinary 17KS and 17OHCS were elevated (Table I). Urinary pregnanetriol excretion was 0.1 rag/24 hours (N = less than 0.5 nag). Urinary excretion of dehydroepiandrosterone was high. normal at 0.5 rag/24 hours, The 24-hour secretion rates for cortisol and aldosterone, carried out while the patient was receiving regular ward diet, were greatly reduced and were 1.7 mg (3 mg/m~/24 hours) (N = 11.3 • 1.6 mg/m2/24 hours) and 0.2 tzg (N = 25-162/xg/24 hours), respectively. 7' 8 A 6-day dexamethasone suppression test 1 was then carried out to exclude an adrenal tumor, using doses of 1 mg every 8 hours. There was complete suppression of adrenal steroid excretion (Table I). Total urinary estrogens were 5.7 /zg/24 hours (normal for adult males) and decreased to 1.7 /zg/24 hours after supp~:ession. Plasma steroid concentrations were measured on an 8:30 AM sample taken before the suppression test. The concentration of plasma total corticoids, measured by competitive binding
580
Brief clinical and laboratory observations
The Journal of Pediatrics April 1975
Table I. T w e n t y - f o u r - h o u r urinary 17-hydroxycorticoids and 17-ketosteroids before and during the six days of dexamethasone administration (in doses of 1 mg every 6 hours)
Before suppression Day 1 Day 2 Day 3 During suppression Day 1 Day 5 Day 6
t
170HCS (rag/24 hr)
17KS (mg/24 hr)
4.2 8.5 6.8
2.6 2.8 3.6
5.4 0.3 0.3
1.3 0.3 0.4
was palpable for the rest of the year. He grew 8.5 cm during the year of treatment and the skeletal age advanced by 1 year. DISCUSSION
Fig. 1. Enlargement of left breast before therapy.
radioassay,7was 39 txg/dl (N =8-18). The plasma ll-desoxycortisol or compound S concentration was 32 /zg/dl (N = 0.78 5:0.53/xg/dl). The plasma DHEA was measured by using an antibody kindly supplied by Dr. Mortimer B. Lipsett from National Institutes of Health. DHEA was extracted with ether, separated from cross-reacting steroids by paper chromatography, and assayed using the same method as for testosterone. 9 For a sample with a mean level of 904 ng/dl, the interassay and intraassay variabilities were 11.8 and 5.6%, respectively. The plasma DHEA concentration in Patient P.M. was 689 /xg/dl (adult male = 109 ___ 20). The plasma testosterone was measured by radioimmunoassay 9 using a variation of the technique of Furuyama and associates.l~ P.M.'s plasma testosterone concentration was 154/xg/dl (adult male = 575 _ 150). Serum follicle-stimulating hormone concentration 13 was 4.0 mlU/ml (N = 4.2 ___ 0.8 mlU/ml) and serum luteinizing hormone concentration [4 was 7.5 mlU/ml and was elevated for age (normal for age = 3.4 +__0.6 rnlU). Therapy was then begun with prednisone in doses of 5 mg three times a day for three weeks followed by maintenance doses of 2,5 nag twice a day for the next year. 15Blood pressure fell to 110/60, and urinary steroids remained suppressed (17KS=1 mg/24 hours and 17OHCS=I rag/24 hours). Gynecomastia regressed within two months. No breast tissue
The initial presentation with gynecomastia, an enlarged penis but normal-sized testes, advanced bone age, hypertension, elevated urinary 17KS and 17OHCS, and normal pregnanetriol excretion led us to suspect that the patient had an adrenal tumor producing both androgens and estrogens. 1, 3, t6,17 His plasma concentration of D H E A was borderline high. However, no renal displacement was seen on the IVP, 3 and the urinary steroids were completely suppressed by dexamethasone (Table I). His elevated plasma hLH concentration may have been secondary to the increase in his production of plasma testosterone. Although the urinary 17OHCS excretion was elev a t e d , the secretion rates of cortisol and aldosterone were later found to be quite low, This suggested a metabolic block in adrenal steroid biosynthesis and this was confirmed by finding greatly elevated plasma l l - d e s oxycortisol ( c o m p o u n d S) concentrations in the plasma, thus identifying the defect as l l - h y d r o x y l a s e deficiency. Such a block may also occur with adrenocortical cancer, but in such patients, the adrenal steroid production is not suppressed by dexamethasone. 18 Displacement of the kidney on the affected side is usually seen by IVP. Moreover, the hypertension and gynecomastia should persist in spite of suppressive therapy, In our patient the gynecomastia was probably due to excessive production of estrogens by the adrenal gland due to increased stimulation by ACTH; it was suppressed by therapy. T h e gynecomastia in this patient was similar to that seen either in early puberty or when testosterone is
Volume 86 Number 4
given to prepubertal boys. His urinary excretion o f estrogen was elevated and was suppressed by therapy. Prepubertal gynecomastia is rare and may be associated with testicular and adrenal tumors or with administration of androgens. 19 We believe this to be the first report of prepubertal gynecomastia found in a boy with untreated congenital adrenal hyperplasia due to 11-hydroxylase deficiency. We wish to thank Mr. Glen E. Taylor for technical assistance with the hFSH and hLH radioimmunoassay, Dr. E. Rosemberg for measurement of the urinary estrogens and The National Pituitary Agency, Department of Pediatrics, University of Maryland School of Medicine and the National Institute of Arthritis Metabolism and Digestive Diseases for the reagents for the hFSH and hLH radioimmunoassay.
REFERENCES 1. Wilkins L: in Blizzard RM, and Migeon CJ, editors: The diagnosis and treatment of endocrine disorders in childhood and adolescence, ed 3, Springfield, IlL, 1965, Charles C Thomas, Publisher, pp 359 and 401-423. 2. Raiti S, and Newns GH: Congenital adrenal hyperplasia, Arch Dis Child 39:324, 1964. 3. Raiti S, Grant DB, Williams DI, and Newns GH: Cush2 ing's syndrome in childhood. Complications and postoperative management, Arch Dis Child 47:597, 1972. 4. Callow NH, Callow RK, and Emmens CW: Colorimetric determination of substances containing the groupingCH2. CO-in 'urine extracts as an indication of androgen content, Biochem J 32:1312, 1938. 5. Glenn EM, and Nelson DH: Chemical method for the determination of 17-hydroxycorticosteroids and 17ketosteroids in urine following hydrolysis with ]3-glucuronidase, J Clin Endocrinol Metab 13:911, 1953. 6. Bongiovanni AM, and Eberlein WE: Critical analysis of methods for measurement of pregnane-3-alpha, 17-alpha, 20-alpha-triol in human urine, Anal Chem 30:388, 1958.
Brief clinical and laboratory observations
581
7. Beitins IZ, Shaw MH, Kowarski A, and Migeon CJ: Comparison of competitive protein-binding radioassay of cortisol to double isotope dilution and Porter-Silber methods, Steriods 15:765, 1970. 8. Keenan BS, Beitins IZ, Lee PA, Kowarski A, Blizzard RM, and Migeon CJ: Estimation of ACTH reserve on normal and hypopituitary subjects: Comparison of oral and intravenous metyrapone with insulin hypoglycemia, J Clin Endocrinol Metab 37:540, 1973. 9. deLacerda L, Lowarski A, Johanson AJ, Athanasion R, and Migeon CJ: Integrated concentration and circadian variation of plasma testosterone in normal men, J Clin Endocrinol Metab 37:366, 1973. 10. Furuyama S, Mayes DM, and Nugent CA: A radioimmunoassay for plasma testosterone, Steroids 16:415, 1970. 11. Migeon CJ, Green OC, and Eckert JP: Study of adrenocortical function in obesity, Metabolism 12:718, 1963. 12. Weldon VV, Kowarski A, Migeon CJ: Aldosterone secretion rates in normal subjects from infancy to adulthood, Pediatrics 39:713, 1967. 13. Raiti S, Johanson A, Light C, Migeon CJ, and Blizzard RM: Measurement of immunologically reactive follicle stimulating hormone in serum of normal male children and adults, Metabolism 18:234, 1969. 14. Johanson AJ, Guyda H, Light C, Migeon CJ, and Blizzard RM: Serum luteinizing hormone by radioimmunoassay in normal children, J PEDIATR74:416, 1969. 15. Raiti S, and Newns GH: Linear growth in treated congenital adrenal hyperplasia, Arch Dis Child 46:376, 1971. 16. Case records of the Massachusetts General Hosptial, N Engl J Med 287:1033, 1972. 17. David R, August G, and Gandy HM: A virilizing adrenal tumor with borderline elevation of urinary 17-ketosteroids, Pediatrics 42:139, 1968. 18. Lipsett MB, and Wilson H: Adrenocortical cancer: Steroid biosynthesis and metabolism evaluated by urinary metabolites, J Clin Invest 22:906, 1962. 19. August GP, Chandra R, and Hung W: Prepubertal male gynecomastia, J PEDIATR80:259, 1972.
strophy of urinary bladder and concomitant malformations; a report based on 82 cases, Pediatrics 23:927, 1959. 17. Greenwood RD, Rosenthal A, Parisi L, Fyler DC, and Nadas AS: Extrffcardiac anomalies in infants with congenital heart disease, Pediatrics (in press). 18. Berdon WE, Hochberg B, Baker DH, Grossman H, and Santulli TV: The association of lumbo-sacral spine and genitourinary anomalies with imperforate anus, A m J Roentgenol 98:181, 1966. 19. Weber FM, Dooley RR, and Sparkes RS: Anal atresia, eye anomalies and an additional small abnormal acrorentcic chromosome (47, XX, Mar +): Report of a case, J PEDIATR76:594, 1970.
Gynecomastia with congenital viril&ing adrenal hyperplasia (11-[3hydroxylase deficiency) Noel K. Maelaren, M.D., Claude J. Migeon, M.D.,
Brief clinical and laboratory observations
579
20.
Kaufman RL, Quintan B, and Ternberg JL: Imperforate anus, vertebral anomalies and preaxial limb abnormalities, Birth Defects 8:85, 1972. 21. Freedom RM, and Gerald PS: Congenital cardiac disease and the Cat Eye syndrome, Am J Dis Child 126:}6, t973. 22. Dupont B, Dupont A, Bliddal J, Hoist E, Melchior JC, and Ottesen OE: Idiopathic hypercalcaemia of infancy. The Elfin face syndrome. Danish Med Bull 17:33, 1970. 23. Tandon R, and Edwards JE: Cardiac malformations associated with Down's Syndrome, Circulation 47:t349, 1973. 24. Welch RG: The Potter syndrome of renal agenesis, Br Med I 1:1102, 1958.
tion (12.7 gm/dl) and normal serum and blood concentrations of urea nitrogen 12 mg/dl, calcium 9.8 mg/dl, phosphorus 6.2 rag/all, sodium 136 mEq/1, potassium 4.9 mEq/1, and alkaline phosphatase 4.5 King-Armstrong units. Serum thyroxine concentration was normal (6.0/zg/dl by Murphy-Pattee method). Skeletal age at the left wrist was 2 years, 8 months (Greulich and Pyle). Skull rOentgenogram was normal. Normal renal outlines with no displacement of the kidneys 3 were noted in an intravenous pyelogram.
and Salvatore Raiti, M.D., Baltimore, Md.
GYNECOMASTIA h a s n o t b e e n d e s c r i b e d in association w i t h u n t r e a t e d c o n g e n i t a l a d r e n a l h y p e r p l a s i a . 1~2 This report deals with a 1-year-old boy who was t h o u g h t initially to h a v e a n a d r e n a l t u m o r , b u t in w h o m a 1 1 - f l - h y d r o x y l a s e d e f i c i e n c y was identified. C A S E REPORT Patient P. M., a 1-year-old black boy presented at the University of Maryland Hospital with unilateral breast enlargement of five month's duration. His general health had been excellent. He was the only child of unrelated black parents in their early twenties. The boy was muscular. Height was 85.5 cm and weight was 13.4 kg (height and weight age for 2 years). He had four teeth. His blood pressure was consistently elevated and ranged from 115/80 to 125/90. Breast tissue was palpable on the left side (3 x 3 cm) but not on the right(Fig. 1). The left areola was enlarged, pointed, and measured 1.7 cm in diameter compared to 1.3 cm on the right side. There was no acne or facial, axillary, or pubic hair. The penis was enlarged with a diameter of 2.5 cm and a stretched length of 6.5 cm. The testes were not enlarged and measured 1.3 x 1.0 cm bilaterally. He had normal fundi and no cushingoid features or organomegaly. The rest of the physical examination was normal. Laboratory data included a normal hemoglobin concentra-
From the Departments of Pediatrics of the University of Maryland School of Medicine and of The Johns Hopkins Hospital
Abbreviations used IVP: intravenous pyelogram 17KS: 17-ketosteroids 17OHCS: 17-hydroxycorticoids DHEA: dehydroepiandrosterone hFSH: serum follicle-stimulating hormone hLH: serum luteinizing hormone Urinary steroids were measured by the following methods: 17-ketosteroids by a modification of the method of Callow and associates 4 17-hydroxycorticoids by modification of the GlennNelson method and pregnanetriol by modification of the technique of Bongiovanni and Eberlein. 6 Baseline concentrations of 24-hour urinary 17KS and 17OHCS were elevated (Table I). Urinary pregnanetriol excretion was 0.1 rag/24 hours (N = less than 0.5 nag). Urinary excretion of dehydroepiandrosterone was high. normal at 0.5 rag/24 hours, The 24-hour secretion rates for cortisol and aldosterone, carried out while the patient was receiving regular ward diet, were greatly reduced and were 1.7 mg (3 mg/m~/24 hours) (N = 11.3 • 1.6 mg/m2/24 hours) and 0.2 tzg (N = 25-162/xg/24 hours), respectively. 7' 8 A 6-day dexamethasone suppression test 1 was then carried out to exclude an adrenal tumor, using doses of 1 mg every 8 hours. There was complete suppression of adrenal steroid excretion (Table I). Total urinary estrogens were 5.7 /zg/24 hours (normal for adult males) and decreased to 1.7 /zg/24 hours after supp~:ession. Plasma steroid concentrations were measured on an 8:30 AM sample taken before the suppression test. The concentration of plasma total corticoids, measured by competitive binding
580
Brief clinical and laboratory observations
The Journal of Pediatrics April 1975
Table I. T w e n t y - f o u r - h o u r urinary 17-hydroxycorticoids and 17-ketosteroids before and during the six days of dexamethasone administration (in doses of 1 mg every 6 hours)
Before suppression Day 1 Day 2 Day 3 During suppression Day 1 Day 5 Day 6
t
170HCS (rag/24 hr)
17KS (mg/24 hr)
4.2 8.5 6.8
2.6 2.8 3.6
5.4 0.3 0.3
1.3 0.3 0.4
was palpable for the rest of the year. He grew 8.5 cm during the year of treatment and the skeletal age advanced by 1 year. DISCUSSION
Fig. 1. Enlargement of left breast before therapy.
radioassay,7was 39 txg/dl (N =8-18). The plasma ll-desoxycortisol or compound S concentration was 32 /zg/dl (N = 0.78 5:0.53/xg/dl). The plasma DHEA was measured by using an antibody kindly supplied by Dr. Mortimer B. Lipsett from National Institutes of Health. DHEA was extracted with ether, separated from cross-reacting steroids by paper chromatography, and assayed using the same method as for testosterone. 9 For a sample with a mean level of 904 ng/dl, the interassay and intraassay variabilities were 11.8 and 5.6%, respectively. The plasma DHEA concentration in Patient P.M. was 689 /xg/dl (adult male = 109 ___ 20). The plasma testosterone was measured by radioimmunoassay 9 using a variation of the technique of Furuyama and associates.l~ P.M.'s plasma testosterone concentration was 154/xg/dl (adult male = 575 _ 150). Serum follicle-stimulating hormone concentration 13 was 4.0 mlU/ml (N = 4.2 ___ 0.8 mlU/ml) and serum luteinizing hormone concentration [4 was 7.5 mlU/ml and was elevated for age (normal for age = 3.4 +__0.6 rnlU). Therapy was then begun with prednisone in doses of 5 mg three times a day for three weeks followed by maintenance doses of 2,5 nag twice a day for the next year. 15Blood pressure fell to 110/60, and urinary steroids remained suppressed (17KS=1 mg/24 hours and 17OHCS=I rag/24 hours). Gynecomastia regressed within two months. No breast tissue
The initial presentation with gynecomastia, an enlarged penis but normal-sized testes, advanced bone age, hypertension, elevated urinary 17KS and 17OHCS, and normal pregnanetriol excretion led us to suspect that the patient had an adrenal tumor producing both androgens and estrogens. 1, 3, t6,17 His plasma concentration of D H E A was borderline high. However, no renal displacement was seen on the IVP, 3 and the urinary steroids were completely suppressed by dexamethasone (Table I). His elevated plasma hLH concentration may have been secondary to the increase in his production of plasma testosterone. Although the urinary 17OHCS excretion was elev a t e d , the secretion rates of cortisol and aldosterone were later found to be quite low, This suggested a metabolic block in adrenal steroid biosynthesis and this was confirmed by finding greatly elevated plasma l l - d e s oxycortisol ( c o m p o u n d S) concentrations in the plasma, thus identifying the defect as l l - h y d r o x y l a s e deficiency. Such a block may also occur with adrenocortical cancer, but in such patients, the adrenal steroid production is not suppressed by dexamethasone. 18 Displacement of the kidney on the affected side is usually seen by IVP. Moreover, the hypertension and gynecomastia should persist in spite of suppressive therapy, In our patient the gynecomastia was probably due to excessive production of estrogens by the adrenal gland due to increased stimulation by ACTH; it was suppressed by therapy. T h e gynecomastia in this patient was similar to that seen either in early puberty or when testosterone is
Volume 86 Number 4
given to prepubertal boys. His urinary excretion o f estrogen was elevated and was suppressed by therapy. Prepubertal gynecomastia is rare and may be associated with testicular and adrenal tumors or with administration of androgens. 19 We believe this to be the first report of prepubertal gynecomastia found in a boy with untreated congenital adrenal hyperplasia due to 11-hydroxylase deficiency. We wish to thank Mr. Glen E. Taylor for technical assistance with the hFSH and hLH radioimmunoassay, Dr. E. Rosemberg for measurement of the urinary estrogens and The National Pituitary Agency, Department of Pediatrics, University of Maryland School of Medicine and the National Institute of Arthritis Metabolism and Digestive Diseases for the reagents for the hFSH and hLH radioimmunoassay.
REFERENCES 1. Wilkins L: in Blizzard RM, and Migeon CJ, editors: The diagnosis and treatment of endocrine disorders in childhood and adolescence, ed 3, Springfield, IlL, 1965, Charles C Thomas, Publisher, pp 359 and 401-423. 2. Raiti S, and Newns GH: Congenital adrenal hyperplasia, Arch Dis Child 39:324, 1964. 3. Raiti S, Grant DB, Williams DI, and Newns GH: Cush2 ing's syndrome in childhood. Complications and postoperative management, Arch Dis Child 47:597, 1972. 4. Callow NH, Callow RK, and Emmens CW: Colorimetric determination of substances containing the groupingCH2. CO-in 'urine extracts as an indication of androgen content, Biochem J 32:1312, 1938. 5. Glenn EM, and Nelson DH: Chemical method for the determination of 17-hydroxycorticosteroids and 17ketosteroids in urine following hydrolysis with ]3-glucuronidase, J Clin Endocrinol Metab 13:911, 1953. 6. Bongiovanni AM, and Eberlein WE: Critical analysis of methods for measurement of pregnane-3-alpha, 17-alpha, 20-alpha-triol in human urine, Anal Chem 30:388, 1958.
Brief clinical and laboratory observations
581
7. Beitins IZ, Shaw MH, Kowarski A, and Migeon CJ: Comparison of competitive protein-binding radioassay of cortisol to double isotope dilution and Porter-Silber methods, Steriods 15:765, 1970. 8. Keenan BS, Beitins IZ, Lee PA, Kowarski A, Blizzard RM, and Migeon CJ: Estimation of ACTH reserve on normal and hypopituitary subjects: Comparison of oral and intravenous metyrapone with insulin hypoglycemia, J Clin Endocrinol Metab 37:540, 1973. 9. deLacerda L, Lowarski A, Johanson AJ, Athanasion R, and Migeon CJ: Integrated concentration and circadian variation of plasma testosterone in normal men, J Clin Endocrinol Metab 37:366, 1973. 10. Furuyama S, Mayes DM, and Nugent CA: A radioimmunoassay for plasma testosterone, Steroids 16:415, 1970. 11. Migeon CJ, Green OC, and Eckert JP: Study of adrenocortical function in obesity, Metabolism 12:718, 1963. 12. Weldon VV, Kowarski A, Migeon CJ: Aldosterone secretion rates in normal subjects from infancy to adulthood, Pediatrics 39:713, 1967. 13. Raiti S, Johanson A, Light C, Migeon CJ, and Blizzard RM: Measurement of immunologically reactive follicle stimulating hormone in serum of normal male children and adults, Metabolism 18:234, 1969. 14. Johanson AJ, Guyda H, Light C, Migeon CJ, and Blizzard RM: Serum luteinizing hormone by radioimmunoassay in normal children, J PEDIATR74:416, 1969. 15. Raiti S, and Newns GH: Linear growth in treated congenital adrenal hyperplasia, Arch Dis Child 46:376, 1971. 16. Case records of the Massachusetts General Hosptial, N Engl J Med 287:1033, 1972. 17. David R, August G, and Gandy HM: A virilizing adrenal tumor with borderline elevation of urinary 17-ketosteroids, Pediatrics 42:139, 1968. 18. Lipsett MB, and Wilson H: Adrenocortical cancer: Steroid biosynthesis and metabolism evaluated by urinary metabolites, J Clin Invest 22:906, 1962. 19. August GP, Chandra R, and Hung W: Prepubertal male gynecomastia, J PEDIATR80:259, 1972.