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International Agency for Research on Cancer (IARC) - Summaries & Evaluations

ANDROGENIC (ANABOLIC) STEROIDS
(Group 2A)

For definition of Groups, see Preamble Evaluation.

Supplement 7: (1987) (p. 96)

Oxymetholone
CAS No.: 437-07-1
Chem. Abstr. Name: 17-Hydroxy-2-(hydroxymethylene)-17-methyl-5a, 17 b-androstan-3-one

Testosterone
CAS No.: 58-22-0
Chem. Abstr. Name: (17b)-17-Hydroxyandrost-4-en-3-one

Testosterone oenanthate
CAS No.: 315-37-7
Chem. Abstr. Name: (17b)-17-[(1-Oxoheptyl)oxy]-androst-4-en-3-one

Testosterone propionate
CAS No.: 57-85-2
Chem. Abstr. Name: (17b)-17-(1-Oxopropoxy)-androst-4-en-3-one

A. Evidence for carcinogenicity to humans (limited)

Cases of benign hepatoma, peliosis hepatis, primary hepatocellular carcinoma and hepatic cholangiocarcinoma have all been linked to the use of androgenic steroids, mostly oxymetholone [ref: 1-13]. At least 25 cases of liver-cell tumour have been reported in patients with Fanconi's anaemia [ref: 1-6,11,12], aplastic anaemia [ref: 1,4,7,8], paroxysmal nocturnal haemoglobinuria [ref: 1,12,13], panmyelopathy [ref: 9] or megaloblastic anaemia [ref: 10] treated with oxymetholone alone or in combination with other androgenic steroid drugs. Usually, treatment was given for years, but cancer has occurred within as little as two months of therapy [ref: 6], and there have been well-documented instances of remission following the withdrawal of oxymetholone treatment [ref: 8,9,11]. Hepatocellular carcinomas were also reported after extended treatment with oxymetholone of one patient with nephrolithiasis [ref: 14] and of another with chronic renal failure [ref: 15]; and hepatocellular carcinomas [ref: 1,16], cholangiocarcinomas [ref: 15] and adenomas [ref: 16] were reported after extended treatment of patients with methyltestosterone, testosterone enanthate and nandrolone decanoate for hypogonadism [ref: 16], hypopituitarism [ref: 13], chronic renal failure [ref: 15] and generalized weakness [ref: 15].

The fact that castration palliates prostatic cancers suggests that testosterone may be involved in the genesis of these tumours [ref: 17], and a number of epidemiological observations suggest that increased testosterone levels may increase the risk for prostatic cancer. In addition, patients with cirrhosis, who have depressed testosterone levels [ref: 18], have low rates of prostatic cancer [ref: 19], and prostatic cancer is seemingly unknown among castrates [ref: 20]. There have also been a number of case reports [ref: 21-23] of prostatic cancer developing after androgen therapy; there was only one, unusual case, however, in which the cancer developed in a 'body-builder' at the age of 40 who had taken anabolic steroids for 18 years [ref: 23].

Blacks in the USA have the highest prostatic cancer rates in the world. Their two-fold increased risk, compared to US whites, is evident at the earliest age at which prostatic cancer occurs. Ross et al. [ref: 24] showed that young US blacks have a 15% higher mean testosterone serum level than young US whites, and argued that this difference could readily explain the two-fold difference in rates.

In one study [ref: 25], prostatic cancer cases were found to have higher mean levels of serum testosterone than healthy controls of the same age. Prostatic cancer cases in this study had a clear excess of high testosterone values. Another study [ref: 26] showed significantly higher levels of serum testosterone in prostatic cancer cases than in age-matched controls among US blacks, but not among African blacks. A number of case-control studies, however, showed no significant difference between cases and controls [ref: 7-29]. At present, there are insufficient data to permit firm conclusions to be drawn.

The development of myeloid leukaemia as a complication of Fanconi's anaemia has been reported in association with the use of oxymetholone [ref: 11,30,31], and there has been one case report of paroxysmal nocturnal haemoglobinuria in which a myeloproliferative disorder developed after oxymetholone therapy [ref: 32].

The evidence that anabolic steroids can cause both benign and malignant liver tumours is quite strong. However, because no analytical epidemiological study has been done, the Working Group felt constrained to classify the evidence for carcinogenicity to humans as no more than 'limited'.

B. Evidence for carcinogenicity to animals (sufficient for testosterone)

Testosterone propionate was tested for carcinogenicity in mice and rats by subcutaneous implantation, producing cervical-uterine tumours in female mice and prostatic adenocarcinomas in male rats. Neonatal treatment of female mice by subcutaneous injection of testosterone induced hyperplastic epithelial lesions of the genital tract and increased the incidence of mammary tumours. 5b-Dihydrotestosterone, which is considered hormonally inactive in adults, also increased the incidence of mammary tumours in mice when given neonatally by subcutaneous injection [ref: 33]. Depots of testosterone propionate implanted in rats resulted in an increased incidence of prostatic adenocarcinomas [ref: 34]. Subcutaneous administration of testosterone propionate following intravenous treatment with N-methyl-N-nitrosourea produced a high incidence of prostatic adenocarcinoma not seen with the individual compounds alone [ref: 35].

No data were available to the Working Group on oxymetholone.

C. Other relevant data

No data were available on the genetic and related effects of testosterone in humans.

Testosterone did not induce sperm abnormalities or micronuclei in mice treated in vivo and was not mutagenic to bacteria [ref: 36].

Overall evaluation

Androgenic (anabolic) steroids are probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 6 (1974); Vol. 13 (1977); Vol. 21 (1979)

References

1. IARC Monographs, 13, 131-139, 1977

2. Port, R.B., Petasnick, J.P. & Ranniger, K. (1971) Angiographic demonstration of hepatome in association with Fanconi's anemia. Am. J. Roentgenol., 113, 82-83

3. Kew, M.C., Van Coller, B., Prowse, C.M., Skikne, B., Wolfsdorf, J.I., Isdale, J., Krawitz, S., Altman, H., Levin, S.E. & Bothwell, T.H. (1976) Occurrence of primary hepatocellular cancer and peliosis hepatis after treatment with androgenic steroids. S.A. med. J., 50, 1233-1237

4. Sweeney, E.C. & Evans, D.J. (1976) Hepatic lesions in patients treated with synthetic anabolic steroids. J. clin. Pathol., 29, 626-633

5. Shapiro, P., Ikede, R.M., Ruebner, B.H., Connors, M.H., Halsted, C.C. & Abildgaard, C.F. (1977) Multiple hepatic tumors and peliosis hepatis in Fanconi's anemia treated with androgens. Am. J. Dis. Child., 131, 1104-1106

6. Mokrohisky, S.T., Ambruso, D.R. & Hathaway, W.E. (1977) Fulminant hepatic neoplasia after androgen therapy. New Engl. J. Med., 296, 1411-1412

7. Sale, G.E. & Lerner, K.G. (1977) Multiple tumors after androgen therapy. Arch. Pathol. Lab. Med., 101, 600-603

8. Montgomery, R.R., Ducore, J.M., Githens, J.H., August, C.S. & Johnson, M.L. (1980) Regression of oxymetholone-induced hepatic tumors after bone marrow transplantation in aplastic anemia. Transplantation, 30, 90-96

9. Treuner, J., Niethammer, D., Flach, A., Fischbach, H. & Schenck, W. (1980) Hepatocellular carcinoma following oxymetholone treatment (Ger.). Med. Welt., 31, 952-955

10. Stromeyer, F.W., Smith, D.H. & Ishak, K.G. (1979) Anabolic steroid therapy and intrahepatic cholangiocarcinoma. Cancer, 43, 440-443

11. Obeid, D.A., Hill, F.G.H., Harnden, D., Mann, J.R. & Wood, B.S.B. (1980) Fanconi anemia. Oxymetholone hepatic tumors, and chromosome aberrations associated with leukemic transition. Cancer, 46, 1401-1404

12. Cap, J., Ondrus, B. & Danihel, L. (1983) Focal nodular hyperplasia of the liver and hepatocellular carcinoma in children with Fanconi's anaemia after long-term treatment with androgen (Czech.). Bratisl. lek. Listy., 79, 73-81

13. McCaughan, G.W., Bilous, M.J. & Gallagher, N.D. (1985) Long-term survival with tumor regression in androgen-induced liver tumors. Cancer, 56, 2622-2626

14. Zevin, D., Turani, H., Cohen, A. & Levi, J. (1981) Androgen-associated hepatoma in a hemodialysis patient. Nephron, 29, 274-276

15. Turani, H., Levi, J., Zevin, D. & Kessler, E. (1983) Hepatic lesions in patients on anabolic androgenic therapy. Isr. J. med. Sci., 19, 322-337

16. Westaby, D., Portmann, B. & Williams, R. (1983) Androgen related primary hepatic tumors in non-Fanconi patients. Cancer, 51, 1947-1952

17. Huggins, C. & Hodges, C.V. (1941) Studies on prostatic cancer. I. The effect of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res., 1, 293-297

18. Gordon, G.G., Altman, K., Southren, A.L., Rubin, E. & Lieber, C.S. (1976) Effect of alcohol (ethanol) administration on sex-hormone metabolism in normal men. New Engl. J. Med., 295, 793-797

19. Glantz, G.M. (1964) Cirrhosis and carcinoma of the prostate gland. J. Urol., 91, 291-293

20. Hovenanian, M.S. & Deming, C.L. (1948) The heterologous growth of cancer of the human prostate. Surg. Gynecol. Obstet., 86, 29-35

21. Sanderman, T.F. (1975) The possible dangers of androgens used for male climacteric. Med. J. Aust., i, 634-635

22. Guinan, P.D., Sadoughi, W., Alsheik, H., Ablin, R.J., Alrenga, D. & Bush, I.M. (1976) Impotence therapy and cancer of the prostate. Am. J. Surg., 131, 599-600

23. Roberts, J.T. & Essenhigh, D.M. (1986) Adenocarcinoma of prostate in a 40-year-old body-builder. Lancet, ii, 742

24. Ross, R., Bernstein, L., Judd, H., Hanisch, R., Pike, M. & Henderson, B. (1986) Serum testosterone levels in healthy young black and white men. J. natl Cancer Inst., 76, 45-48

25. Ghanadian, R., Puah, C.M. & O'Donoghue, E.P.N. (1979) Serum testosterone and dihydrotestosterone in carcinoma of the prostate. Br. J. Cancer, 39, 696-699

26. Ahluwalia, B., Jackson, M.A., Jones, G.W., Williams, A.O., Rao, M.S. & Rajguru, S. (1981) Blood hormone profiles in prostate cancer patients in high-risk and low-risk populations. Cancer, 48, 2267-2273

27. Hammond, G.L., Kontturi, M., Vihko, P. & Vihko, R. (1978) Serum steroids in normal males and patients with prostatic diseases. Clin. Endocrinol., 9, 113-121

28. Bartsch, W., Steins, P. & Becker, H. (1977) Hormone blood levels in patients with prostatic carcinoma and their relationship to the type of carcinoma growth differentiation. Eur. Urol., 3, 47-52

29. Harper, M.E., Peeling, W.B., Cowley, T., Brownsey, B.G., Phillips, M.E.A., Groom, G., Fahmy, D.R. & Griffiths, K. (1976) Plasma steroid and protein hormone concentrations in patients with prostatic carcinoma, before and during oestrogen therapy. Acta endocrinol., 81, 409-426

30. Sarna, G., Tomasulo, P., Lotz, M.J., Bubinak, J.F. & Shulman, N.R. (1975) Multiple neoplasms in two siblings with a variant form of Fanconi's anemia. Cancer, 36, 1029-1033

31. Bourgeois, C.A. & Hill, F.G.H. (1977) Fanconi's anemia leading to acute myelomonocytic leukemia. Cytogenic studies. Cancer, 39, 1163-1167

32. Boyd, A.W., Parkin, J.D. & Castaldi, P.A. (1979) A case of paroxysmal nocturnal haemoglobinuria terminating in a myeloproliferative syndrome. Aust. N.Z. J. Med., 9, 181-183

33. IARC Monographs, 21, 519-547, 1979

34. Pollard, M. & Luckert, P.H. (1986) Promotional effects of testosterone and high fat diet on the development of autochthonous prostate cancer in rats. Cancer Lett., 32, 223-227

35. Pollard, M. & Luckert, P.H. (1986) Production of autochthonous prostate cancer in Lobund-Wistar rats by treatment with N-nitroso-N-methylurea and testosterone. J. natl Cancer Inst., 77, 583-587

36. IARC Monographs, Suppl. 6, 506-507, 1987

Synonyms for Oxymetholone:

Synonyms for Testosterone

Synonyms for Testosterone oenanthate

Synonyms for Testosterone proprionate


Last updated: 11 February 1998






















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       Toxicological Abbreviations