Letters in the NEJM:
In 1993, an article was published in the New England Journal of Medicine about gynecomastia that prompted responses from the medical community. While the article is not available on line, the responses are and are republished here because they do provide additional information, especially from the author, Dr. Braunstein. - Phoenix5 Webmaster
July 15, 1993 -- Vol. 329, No. 3
To the Editor:
In his review of gynecomastia (Feb. 18 issue), (1) Dr. Braunstein includes a long and detailed list of agents that have the potential to induce the condition. Human growth hormone was not listed. Although not widely known, it has been reported that growth hormone can induce gynecomastia (2). The underlying mechanisms are not known, but may be related to the lactogenic activity of growth hormone.
Recombinant techniques have provided an unlimited supply of growth hormone, and many patients without growth hormone deficiency are being treated with the hormone. Physicians should be aware that gynecomastia is a potential side effect of therapy with growth hormone.
Saul Malozowski, M.D., Ph.D.
Food and Drug Administration
Rockville, MD 20857
Braunstein GD. Gynecomastia. N Engl J Med 1993;328:490-5.
Rudman D, Feller AG, Cohn L, Shetty KR, Rodman IW, Draper MW. Effects of human growth hormone on body composition in elderly men. Horm Res 1991;36:Suppl 1:73-81.
To the Editor:
Braunstein recommends treatment with the antiestrogen tamoxifen in patients with painful gynecomastia of recent onset, "in view of the safety of the drug." Tamoxifen is chemically related to diethylstilbestrol, which was once also believed to be safe. The preclinical studies with tamoxifen do not establish its safety (1) and have not been published in the literature. Tamoxifen is a strong liver carcinogen in female rats, (2, 3) stronger in fact than diethylstilbestrol (4). Data from clinical trials of tamoxifen reveal some increases in the number of tumors (i.e., endometrium and liver) in some studies, but for the most part have not shown a strong carcinogenic effect. The data, however, are not sufficient to preclude carcinogenicity. Physicians should be aware of these issues and realize that there is a related antiestrogen, toremifene, that has not induced liver cancer in rodents.
Gary M. Williams, M.D.
American Health Foundation
Valhalla, NY 10595
Physicians' desk reference. 45th ed. Oradell, N.J.: Medical Economics Data, 1991:1070-2.
Williams GM, Iatropoulos MJ, Hard GC. Long-term prophylactic use of tamoxifen: is it safe? Eur J Cancer Prev 1992;1:386-7.
Williams GM, Iatropoulos MJ, Djordjevic MV, Kaltenberg OP. The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis 1993;14:315-7.
Williams GM, Iatropoulos M, Cheung R, Radi L, Wang CX. Diethylstilbestrol liver carcinogenicity and modification of DNA in rats. Cancer Lett 1993;68:193-8.
Dr. Braunstein replies:
To the Editor:
In the paper cited by Dr. Malozowski, Rudman and coworkers studied men between the ages of 61 and 81 who had low levels of plasma insulin-like growth factor I (somatomedin C), presumably reflecting diminished secretion of growth hormone (1). Four of the 26 subjects who received biosynthetic growth hormone in doses sufficient to increase their somatomedin C levels had gynecomastia two to seven months after beginning therapy, whereas none of the 19 control patients had breast enlargement. The gynecomastia resolved in three patients after growth hormone was discontinued. In the other patient, the gynecomastia remitted despite continued therapy with growth hormone. The authors speculated that gynecomastia was the result of the lactogenic property of growth hormone. It is more likely that in these men selected for inadequate secretion of growth hormone, the exogenous growth hormone increased the sensitivity of the testicular Leydig cells to gonadotropins, a phenomenon previously demonstrated in boys with hypopituitarism (2). Growth hormone is currently being studied as an anabolic agent for a number of medical illnesses in adults. It should be possible to determine whether growth hormone therapy will be associated with gynecomastia in men who do not have growth hormone deficiency at the start of treatment.
Dr. Williams questions the use of tamoxifen as a medical therapy for gynecomastia because he believes that the carcinogenic effects of the drug in humans have not been adequately studied. Although tamoxifen induces liver tumors in some strains of rats, the data are difficult to extrapolate to humans. In fact, in the several studies that have examined the occurrence of new primary tumors in women receiving adjuvant tamoxifen therapy for breast cancer, no increase in the incidence of liver cancer has been noted (3,4,5,6). A review of a data base maintained by the manufacturer of tamoxifen shows that only two cases of liver cancer have been reported during an estimated 4.5 million patient-years of exposure to tamoxifen (Smith MC, Zeneca Pharmaceuticals Group, Wilmington, Del.: personal communication). Furthermore, it should be noted that my recommendation for the use of tamoxifen in patients with painful gynecomastia of recent onset was limited to a three-month course. This is a substantially shorter period of drug exposure than that described in the trials of adjuvant tamoxifen for breast cancer, which have established the low carcinogenic potential of the drug.
Glenn D. Braunstein, M.D.
Cedars-Sinai Medical Center
Los Angeles, CA 90048
Rudman D, Feller AG, Cohn L, Shetty KR, Rudman IW, Draper MW. Effects of human growth hormone on body composition in elderly men. Horm Res 1991;36:Suppl 1:73-81.
Kulin HE, Samojlik E, Santen R, Santner S. The effect of growth hormone on the Leydig cell response to chorionic gonadotrophin in boys with hypopituitarism. Clin Endocrinol (Oxf) 1981;15:463-72.
Ribeiro G, Swindell R. The Christie Hospital Adjuvant Tamoxifen Trial -- status at 10 years. Br J Cancer 1988;57:601-3.
Fornander T, Rutqvist LE, Cedermark B, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989;1:117-20.
Stewart HJ, Knight GM. Tamoxifen and the uterus and endometrium. Lancet 1989;1:375-6.
Andersson M, Storm HH, Mouridsen HT. Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer. J Natl Cancer Inst 1991;83:1013-7.