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Prepubertal gynecomastia during growth hormone therapy
The Journal of Pediatrics Volume 126, Number 4
3. Sury M, Billingham I, Russel G, Hopkins C, Thorington R, Viviori E. Acute benzodiazepine withdrawal syndrome after midazolam infusions in children [Letter]. Crit Care Med 1989;17:301-2. 4. Gennaro A, ed. Remington's pharmaceutical sciences. 18th ed. Easton, Pennsylvania:Mack Publishing, 1990:219, 1317.
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5. Benitz W, Tatro D. The pediatric drug handbook. 2nd ed. Chicago: Year Book Medical Publishers, 1988:85-6, 108-9. 6. American Academy of Pediatrics Committee on Drugs. "Inactive" ingredients in pharmaceutical products. Pediatrics 1985;76:635-43.
Prepubertal gynecomastia during growth hormone therapy Saul M a l o z o w s k i , MD, PhD, a n d Bruce V. S t a d e l , MD, MPH From the Division of Metabolism and Endocrine Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland
We report 22 cases of prepubertal gynecomastia diagnosed during growth hormone (GH) treatment. The age and dose range were 2 to 12 years and 1.8 to 0.3 mg/kg per week, respectively. In most of the patients, gynecomastia appeared between 0.5 and 7 months after GH was started. Three boys were using drugs other than GH. This condition appears to be self-limited and benign. (J PEDIATR 1995;126:659-61)
Gynecomastia occurs in about 70% of boys during puberty, 1 but prepubertal gynecomastia is rare. 2 When gynecomastia does occur before puberty, there is usually evidence of endogenous or exogenous estrogenic stimulation.37 To our knowledge, drugs other than sex steroids have not been associated with prepubertal gynecomastia, although many drugs have been related to its occurrence in adults. 8 In this report, we describe 22 cases of gynecomastia that developed before puberty in boys treated with growth hormone. METHODS Cases of gynecomastia diagnosed during GH treatment of prepubertal boys were identified by reviewing "adverse drug experience" reports to the U.S. Food and Drug Administration. We defined "prepubertal" as a reported age of _<12 years and, if recorded, Tanner stage I or testicular volume --<2 ml or both. Neonatal gynecomastia was excluded by requiring that the age be -->2 years. The first
The contents of this manuscript represent the views of the authors and do not constitute an officialpositionof the U.S. Food and Drug Administration. Submitted for publication Aug. 12, 1994; accepted Oct. 6, 1994. Reprint requests: Saul Malozowski, MD, PhD, U.S. Food and Drug Administration, HFD-510, Room 14B-03, Rockville, MD 20857. 9/26/61102
six cases meeting these criteria were found by searching the existing adverse drug experience database of the Food and Drug Administration. Subsequent inquiries to pharmaceutical companies that market GH domestically and abroad led to the reporting of 16 additional cases. RESULTS We identified 22 cases of prepubertal gynecomastia that were diagnosed during GH treatment. All boys were 2 to 12 years of age at diagnosis, with a median age of 7 years. Five were described as in Tanner stage I with testicular volume ___2ml, five as being in Tanner stage I with no data on tesGH
Growthhormone
ticular volume, and two as having a testicular volume _<2 ml with no data on Tanner stage. Ten cases were reported with no data on Tanner stage or testicular volume; the age range for this subgroup was 2 to 12 years (median, 7 years). The cases were reported from the United States and Europe, with no evidence of geographic clustering. The diagnosis leading to GH treatment was reported to be GH deficiency in 18 cases; the other four were cases of short stature--one with intrauterine growth retardation, one with Noonan syndrome, one with Aarskog syndrome, and one with a GH neurosecretory disorder. One boy with GH deficiency also had asthma and allergic rhinitis, one had
660
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cryptorchidism (age 7 years, Tanner stage and testicular volume unreported), one had rickets, and one had undergone bone marrow transplantation at 2t/2 years of age for acute lymphoblastic leukemia, with complications of hostversus-graft disease and scleroderma. No current medications other than G H were reported except for three patients--one taking ketotifen (a histamine receptor antagonist), theophylline, and cromolyn sodium for asthma; one taking vitamin D for rickets; and one taking thyroid hormone. The GH dose ranged from approximately 1.8 to 0.3 mg/kg per week, by subcutaneous injection, for the 16 cases with dosages reported. The time from the start of GH therapy to diagnosis of gynecomastia ranged from 0.5 to 7 months for 13 cases and from 1 to 8 years for eight; the interval was not stated for one. The gynecomastia was unilateral in nine boys and bilateral in seven; laterality was not stated for six. Mammary size was reported for three patients--as 1, 2, and 5 cm. One boy was described as having increased areolar pigmentation, but none was reported to have spontaneous or induced mammary discharge. Hormonal determinations were available in eight cases. Serum estrogen, testosterone, and prolactin concentrations were determined in most of these cases; all results were within normal limits for age and sex. No other laboratory abnormalities were reported, except for liver enzyme elevations in the one patient with Aarskog syndrome. In one boy the gynecomastia resolved within 3 months after GH therapy was stopped, but it reappeared when GH therapy was restarted. In another, the gynecomastia also resolved after treatment with GH was stopped, but no information was given about whether treatment was restarted. In five patients the gynecomastia regressed spontaneously while administration of GH was continued. No information is available about the clinical evolution of the other cases. DISCUSSION Our findings are in accordance with those of Rudman et al., 9 who reported the occurrence of gynecomastia in 4 of 26 elderly men treated with GH in a clinical trial. Their four cases all appeared between 2 and 7 months after GH therapy was started; three resolved after treatment was stopped, and one resolved spontaneously while GH therapy was continued. In addition, regression of breast symptoms after the administration of GH-inhibiting drugs has been described in a patient with gynecomastia and lung cancer, who had elevated GH levels. 1° Thus the role of GH in the development of gynecomastia appears well substantiated in adult men.
Tanner staging or testicular volume, or both, in 12 of our patients indicated their prepubertal status, and one boy
The Journal of Pediatrics April 1995
without this information was reported as having cryptorchidism. Although data on sexual maturity were not available for the remaining nine patients, we believe that they were also prepubertal because their age range was 2 to 12 years, and puberty tends to be delayed in GH-deficient childrenJ ~ Pubertal gynecomastia usually appears when puberty has advanced to Tanner stage III-IV (ages 14 and 15 years). 12 The mechanism underlying stimulation of gynecomastia by GH has not been established. However, GH receptors have been identified in human breast cell lines, 13 and GH could be stimulating growth directly through these, or through lactogenic receptors] 4 or indirectly through the production of insulin-like growth factor] 5 In this study, plasma levels of estradiol were within normal limits in all eight patients with levels reported. We cannot estimate the incidence of prepubertal gynecomastia during GH treatment, because we do not have data on the number of boys _< 12 years of age who have been treated with GH in the countries from which our adverse drug experience reports came, and because substantial underreporting is likely even with our efforts to solicit data on known cases. However, in 1983 Haibach et al. 2 were able to identify only 43 published case reports of prepubertal gynecomastia, and in 1985 Descamps et al. 16 reported only 16 additional cases, of which 13 were described as "idiopathic." Our finding of 22 cases associated specifically with GH therapy seems large in this context. In addition, gynecomastia was first detected in 63% of the cases in the first 6 months of therapy; the lack of an even time distribution suggests that this association is drug related and that it is more commonly seen soon after GH is initially given. We have not identified any reports of premature thelarche in prepubertal girls treated with GH. Although our findings indicate that the course of GH-induced gynecomastia in prepubertal boys is time limited and benign, breast examinations should be performed routinely in patients receiving GH. REFERENCES
1. Nydick M, Bustos J, Dale J, Rawson RW. Gynecomastia in adolescent boys. JAMA 1961;178:449-54. 2. Haibach H, Rosebholtz MJ. Prepubertal gynecomastia with lobules and acini: a case report and review of the literature. Am J Clin Pathol 1983;80:252-5. 3. Hemsell DL, Edman CD, Marks JF, Siiteri PK, MacDonald PC. Massive extraglandular aromatization of plasma androstenedione resulting in feminization of a prepubertal boy. J Clin Invest 1977;60:455-64. 4. Payne AH, Perkins LM, Giorgiou M, Quinn PG. Intratesticular aromatase site of activity and possible function of testicular estradiol. Steroids 1987;50:435-48. 5, Brodie A, Inkster S. Aromatase in the human testis. J Steroid Biochem Mol Biol 1993;44:549-55.
The Journal of Pediatrics Volume 126, Number 4
Malozowski and Stadel
6. Bhettay E, Bonnici F. Pure oestrogen-secreting feminizing adrenocortical adenoma. Arch Dis Child 1977;52:241-3. 7. Edidin DV. Prcpubertal gynecomastia associated with estrogen-containing hair cream. Am J Dis Child 1982;136:587-8. 8. Braunstein GD. Gynecomastia. N Engl J Med 1993;328:490505. 9. Rudman D, Feller AG, Cohn L, Shetty KR, Rudman IW, Draper MW. Effects of human growth hormone in body composition in elderly men. Horm Res 1991;36(suppl 1):73-81. 10. Matucci Cerinic M. Response of hypertrophic osteoarthropathy to drugs inhibiting growth hormone [Letter]. J Reumathol 1984; 1l:865-6. 11. Goodman HG, Grumbach MM, Kaplan SL. Growth and growth hormone. II. A comparisonof isolated growth hormone deficiencyand multiple pituitary-hormone deficiencyin 35 patients with idiopathic pituitary dwarfism. N Engl J Med 1968; 278:57-68.
661
12. Biro FM, Lucky AW, Huster GA, Morrison JA. Hormonal studies and physical maturation in adolescent gynecomastia.J PEDIATR 1990;116:450-5. 13. Murphy LJ, Murphy LC, Stead B, Sutherland RL, Lazarus L. Modulation of lactogenic receptors by progestins in cultured human breast cancer cells. J Clin Endocrinol Metab 1986;62:280-7. 14. Fradkin JE, Eastman RC, Lesniak MA, Roth J. Specificity spillover at the hormone receptor: exploring its role in human disease. N Engl J Med 1989;320:640-5. 15. RosenN, Yee D, Lippman ME, Paik S, Cullen KJ. Insulin-like growth factors in human breast cancer. Breast Cancer Res Treat 1991;18:$55-62. 16. Descamps H, Chaussain JL, Job JC. Les gynecomasties du garcon avant la puberte. Arch Fr Pediatr 1985;42:87-9.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of THE JOURNAL OF PEDIATRICS for the preceding 5 years are maintained and are available for purchase from the publisher, Mosby-Year Book, Inc., at a cost of $10.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to MosbyYear Book, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis MO 631463318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If back issues are unavailable from the publisher, photocopies of complete issues are available from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.
3. Sury M, Billingham I, Russel G, Hopkins C, Thorington R, Viviori E. Acute benzodiazepine withdrawal syndrome after midazolam infusions in children [Letter]. Crit Care Med 1989;17:301-2. 4. Gennaro A, ed. Remington's pharmaceutical sciences. 18th ed. Easton, Pennsylvania:Mack Publishing, 1990:219, 1317.
Malozowski and StadeI
659
5. Benitz W, Tatro D. The pediatric drug handbook. 2nd ed. Chicago: Year Book Medical Publishers, 1988:85-6, 108-9. 6. American Academy of Pediatrics Committee on Drugs. "Inactive" ingredients in pharmaceutical products. Pediatrics 1985;76:635-43.
Prepubertal gynecomastia during growth hormone therapy Saul M a l o z o w s k i , MD, PhD, a n d Bruce V. S t a d e l , MD, MPH From the Division of Metabolism and Endocrine Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland
We report 22 cases of prepubertal gynecomastia diagnosed during growth hormone (GH) treatment. The age and dose range were 2 to 12 years and 1.8 to 0.3 mg/kg per week, respectively. In most of the patients, gynecomastia appeared between 0.5 and 7 months after GH was started. Three boys were using drugs other than GH. This condition appears to be self-limited and benign. (J PEDIATR 1995;126:659-61)
Gynecomastia occurs in about 70% of boys during puberty, 1 but prepubertal gynecomastia is rare. 2 When gynecomastia does occur before puberty, there is usually evidence of endogenous or exogenous estrogenic stimulation.37 To our knowledge, drugs other than sex steroids have not been associated with prepubertal gynecomastia, although many drugs have been related to its occurrence in adults. 8 In this report, we describe 22 cases of gynecomastia that developed before puberty in boys treated with growth hormone. METHODS Cases of gynecomastia diagnosed during GH treatment of prepubertal boys were identified by reviewing "adverse drug experience" reports to the U.S. Food and Drug Administration. We defined "prepubertal" as a reported age of _<12 years and, if recorded, Tanner stage I or testicular volume --<2 ml or both. Neonatal gynecomastia was excluded by requiring that the age be -->2 years. The first
The contents of this manuscript represent the views of the authors and do not constitute an officialpositionof the U.S. Food and Drug Administration. Submitted for publication Aug. 12, 1994; accepted Oct. 6, 1994. Reprint requests: Saul Malozowski, MD, PhD, U.S. Food and Drug Administration, HFD-510, Room 14B-03, Rockville, MD 20857. 9/26/61102
six cases meeting these criteria were found by searching the existing adverse drug experience database of the Food and Drug Administration. Subsequent inquiries to pharmaceutical companies that market GH domestically and abroad led to the reporting of 16 additional cases. RESULTS We identified 22 cases of prepubertal gynecomastia that were diagnosed during GH treatment. All boys were 2 to 12 years of age at diagnosis, with a median age of 7 years. Five were described as in Tanner stage I with testicular volume ___2ml, five as being in Tanner stage I with no data on tesGH
Growthhormone
ticular volume, and two as having a testicular volume _<2 ml with no data on Tanner stage. Ten cases were reported with no data on Tanner stage or testicular volume; the age range for this subgroup was 2 to 12 years (median, 7 years). The cases were reported from the United States and Europe, with no evidence of geographic clustering. The diagnosis leading to GH treatment was reported to be GH deficiency in 18 cases; the other four were cases of short stature--one with intrauterine growth retardation, one with Noonan syndrome, one with Aarskog syndrome, and one with a GH neurosecretory disorder. One boy with GH deficiency also had asthma and allergic rhinitis, one had
660
Malozowski and Stadel
cryptorchidism (age 7 years, Tanner stage and testicular volume unreported), one had rickets, and one had undergone bone marrow transplantation at 2t/2 years of age for acute lymphoblastic leukemia, with complications of hostversus-graft disease and scleroderma. No current medications other than G H were reported except for three patients--one taking ketotifen (a histamine receptor antagonist), theophylline, and cromolyn sodium for asthma; one taking vitamin D for rickets; and one taking thyroid hormone. The GH dose ranged from approximately 1.8 to 0.3 mg/kg per week, by subcutaneous injection, for the 16 cases with dosages reported. The time from the start of GH therapy to diagnosis of gynecomastia ranged from 0.5 to 7 months for 13 cases and from 1 to 8 years for eight; the interval was not stated for one. The gynecomastia was unilateral in nine boys and bilateral in seven; laterality was not stated for six. Mammary size was reported for three patients--as 1, 2, and 5 cm. One boy was described as having increased areolar pigmentation, but none was reported to have spontaneous or induced mammary discharge. Hormonal determinations were available in eight cases. Serum estrogen, testosterone, and prolactin concentrations were determined in most of these cases; all results were within normal limits for age and sex. No other laboratory abnormalities were reported, except for liver enzyme elevations in the one patient with Aarskog syndrome. In one boy the gynecomastia resolved within 3 months after GH therapy was stopped, but it reappeared when GH therapy was restarted. In another, the gynecomastia also resolved after treatment with GH was stopped, but no information was given about whether treatment was restarted. In five patients the gynecomastia regressed spontaneously while administration of GH was continued. No information is available about the clinical evolution of the other cases. DISCUSSION Our findings are in accordance with those of Rudman et al., 9 who reported the occurrence of gynecomastia in 4 of 26 elderly men treated with GH in a clinical trial. Their four cases all appeared between 2 and 7 months after GH therapy was started; three resolved after treatment was stopped, and one resolved spontaneously while GH therapy was continued. In addition, regression of breast symptoms after the administration of GH-inhibiting drugs has been described in a patient with gynecomastia and lung cancer, who had elevated GH levels. 1° Thus the role of GH in the development of gynecomastia appears well substantiated in adult men.
Tanner staging or testicular volume, or both, in 12 of our patients indicated their prepubertal status, and one boy
The Journal of Pediatrics April 1995
without this information was reported as having cryptorchidism. Although data on sexual maturity were not available for the remaining nine patients, we believe that they were also prepubertal because their age range was 2 to 12 years, and puberty tends to be delayed in GH-deficient childrenJ ~ Pubertal gynecomastia usually appears when puberty has advanced to Tanner stage III-IV (ages 14 and 15 years). 12 The mechanism underlying stimulation of gynecomastia by GH has not been established. However, GH receptors have been identified in human breast cell lines, 13 and GH could be stimulating growth directly through these, or through lactogenic receptors] 4 or indirectly through the production of insulin-like growth factor] 5 In this study, plasma levels of estradiol were within normal limits in all eight patients with levels reported. We cannot estimate the incidence of prepubertal gynecomastia during GH treatment, because we do not have data on the number of boys _< 12 years of age who have been treated with GH in the countries from which our adverse drug experience reports came, and because substantial underreporting is likely even with our efforts to solicit data on known cases. However, in 1983 Haibach et al. 2 were able to identify only 43 published case reports of prepubertal gynecomastia, and in 1985 Descamps et al. 16 reported only 16 additional cases, of which 13 were described as "idiopathic." Our finding of 22 cases associated specifically with GH therapy seems large in this context. In addition, gynecomastia was first detected in 63% of the cases in the first 6 months of therapy; the lack of an even time distribution suggests that this association is drug related and that it is more commonly seen soon after GH is initially given. We have not identified any reports of premature thelarche in prepubertal girls treated with GH. Although our findings indicate that the course of GH-induced gynecomastia in prepubertal boys is time limited and benign, breast examinations should be performed routinely in patients receiving GH. REFERENCES
1. Nydick M, Bustos J, Dale J, Rawson RW. Gynecomastia in adolescent boys. JAMA 1961;178:449-54. 2. Haibach H, Rosebholtz MJ. Prepubertal gynecomastia with lobules and acini: a case report and review of the literature. Am J Clin Pathol 1983;80:252-5. 3. Hemsell DL, Edman CD, Marks JF, Siiteri PK, MacDonald PC. Massive extraglandular aromatization of plasma androstenedione resulting in feminization of a prepubertal boy. J Clin Invest 1977;60:455-64. 4. Payne AH, Perkins LM, Giorgiou M, Quinn PG. Intratesticular aromatase site of activity and possible function of testicular estradiol. Steroids 1987;50:435-48. 5, Brodie A, Inkster S. Aromatase in the human testis. J Steroid Biochem Mol Biol 1993;44:549-55.
The Journal of Pediatrics Volume 126, Number 4
Malozowski and Stadel
6. Bhettay E, Bonnici F. Pure oestrogen-secreting feminizing adrenocortical adenoma. Arch Dis Child 1977;52:241-3. 7. Edidin DV. Prcpubertal gynecomastia associated with estrogen-containing hair cream. Am J Dis Child 1982;136:587-8. 8. Braunstein GD. Gynecomastia. N Engl J Med 1993;328:490505. 9. Rudman D, Feller AG, Cohn L, Shetty KR, Rudman IW, Draper MW. Effects of human growth hormone in body composition in elderly men. Horm Res 1991;36(suppl 1):73-81. 10. Matucci Cerinic M. Response of hypertrophic osteoarthropathy to drugs inhibiting growth hormone [Letter]. J Reumathol 1984; 1l:865-6. 11. Goodman HG, Grumbach MM, Kaplan SL. Growth and growth hormone. II. A comparisonof isolated growth hormone deficiencyand multiple pituitary-hormone deficiencyin 35 patients with idiopathic pituitary dwarfism. N Engl J Med 1968; 278:57-68.
661
12. Biro FM, Lucky AW, Huster GA, Morrison JA. Hormonal studies and physical maturation in adolescent gynecomastia.J PEDIATR 1990;116:450-5. 13. Murphy LJ, Murphy LC, Stead B, Sutherland RL, Lazarus L. Modulation of lactogenic receptors by progestins in cultured human breast cancer cells. J Clin Endocrinol Metab 1986;62:280-7. 14. Fradkin JE, Eastman RC, Lesniak MA, Roth J. Specificity spillover at the hormone receptor: exploring its role in human disease. N Engl J Med 1989;320:640-5. 15. RosenN, Yee D, Lippman ME, Paik S, Cullen KJ. Insulin-like growth factors in human breast cancer. Breast Cancer Res Treat 1991;18:$55-62. 16. Descamps H, Chaussain JL, Job JC. Les gynecomasties du garcon avant la puberte. Arch Fr Pediatr 1985;42:87-9.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of THE JOURNAL OF PEDIATRICS for the preceding 5 years are maintained and are available for purchase from the publisher, Mosby-Year Book, Inc., at a cost of $10.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to MosbyYear Book, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis MO 631463318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If back issues are unavailable from the publisher, photocopies of complete issues are available from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.