Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 1989 Jul;60(1):107–111. doi: 10.1038/bjc.1989.231

Alterations in the production rate and the metabolism of oestrone and oestrone sulphate in breast cancer patients treated with aminoglutethimide.

P E Lønning 1, D C Johannessen 1, T Thorsen 1
PMCID: PMC2247335  PMID: 2553085

Abstract

Plasma level, plasma clearance, production rate and interconversions of oestrone and oestrone sulphate were measured in six breast cancer patients receiving aminoglutethimide therapy. Three additional patients had the production rate of oestrone sulphate investigated. Plasma oestrone and oestrone sulphate levels were reduced by a mean of 46% (P less than 0.05) and 71% (P less than 0.005) respectively. These alterations were due to a combined action of aminoglutethimide inhibiting oestrogen production but also increasing oestrogen metabolism. While oestrone and oestrone sulphate production rate was reduced by a mean of 31% (P less than 0.05) and 41% (P less than 0.005) respectively, the plasma clearance rate of oestrone was found to be increased by a mean of 30% (P less than 0.05), and the plasma clearance rate of oestrone sulphate was increased by a mean of 112% during aminoglutethimide treatment. The fraction of oestrone sulphate converted into plasma oestrone was reduced by 52% (P less than 0.05), the transfer of circulating oestrone into sulphate was non-significantly reduced by a mean of 16%. The findings in this investigation show that aminoglutethimide treatment influences oestrogen disposition by mechanisms unrelated to aromatase inhibition. The possibility that such effects might be partly responsible for the mechanism of action of aminoglutethimide in advanced breast cancer should be considered.

Full text

PDF

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baird D. T., Guevara A. Concentration of unconjugated estrone and estradiol in peripheral plasma in nonpregnant women throughout the menstrual cycle, castrate and postmenopausal women and in men. J Clin Endocrinol Metab. 1969 Feb;29(2):149–156. doi: 10.1210/jcem-29-2-149. [DOI] [PubMed] [Google Scholar]
  2. Dowsett M., Harris A. L., Stuart-Harris R., Hill M., Cantwell B. M., Smith I. E., Jeffcoate S. L. A comparison of the endocrine effects of low dose aminoglutethimide with and without hydrocortisone in postmenopausal breast cancer patients. Br J Cancer. 1985 Oct;52(4):525–529. doi: 10.1038/bjc.1985.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. GURPIDE E., MANN J., LIEBERMAN S. ANALYSIS OF OPEN SYSTEMS OF MULTIPLE POOLS BY ADMINISTRATION OF TRACERS AT A CONSTANT RATE OR AS A SINGLE DOSE AS ILLUSTRATED BY PROBLEMS INVOLVING STEROID HORMONES. J Clin Endocrinol Metab. 1963 Nov;23:1155–1176. doi: 10.1210/jcem-23-11-1155. [DOI] [PubMed] [Google Scholar]
  4. Grodin J. M., Siiteri P. K., MacDonald P. C. Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab. 1973 Feb;36(2):207–214. doi: 10.1210/jcem-36-2-207. [DOI] [PubMed] [Google Scholar]
  5. Gundersen S., Kvinnsland S., Klepp O., Kvaløy S., Lund E., Høst H. Weekly adriamycin versus VAC in advanced breast cancer. A randomized trial. Eur J Cancer Clin Oncol. 1986 Dec;22(12):1431–1434. doi: 10.1016/0277-5379(86)90075-1. [DOI] [PubMed] [Google Scholar]
  6. Harris A. L., Dowsett M., Jeffcoate S. L., Smith I. E. Aminoglutethimide dose and hormone suppression in advanced breast cancer. Eur J Cancer Clin Oncol. 1983 Apr;19(4):493–498. doi: 10.1016/0277-5379(83)90112-8. [DOI] [PubMed] [Google Scholar]
  7. Harris A. L., Dowsett M., Smith I. E., Jeffcoate S. Hydrocortisone alone vs hydrocortisone plus aminoglutethimide: a comparison of the endocrine effects in postmenopausal breast cancer. Eur J Cancer Clin Oncol. 1984 Apr;20(4):463–469. doi: 10.1016/0277-5379(84)90230-x. [DOI] [PubMed] [Google Scholar]
  8. Hembree W. C., Bardin C. W., Lipsett M. B. A study of estrogen metabolic clearance rates and transfer factors. J Clin Invest. 1969 Oct;48(10):1809–1819. doi: 10.1172/JCI106147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Judd H. L., Shamonki I. M., Frumar A. M., Lagasse L. D. Origin of serum estradiol in postmenopausal women. Obstet Gynecol. 1982 Jun;59(6):680–686. [PubMed] [Google Scholar]
  10. Kirschner M. A., Cohen F. B., Ryan C. Androgen-estrogen production rates in postmenopausal women with breast cancer. Cancer Res. 1978 Nov;38(11 Pt 2):4029–4035. [PubMed] [Google Scholar]
  11. Kvinnsland S., Lønning P. E., Dahl O. Treatment of breast carcinoma with aminoglutethimide. Acta Radiol Oncol. 1984;23(6):421–424. doi: 10.3109/02841868409136042. [DOI] [PubMed] [Google Scholar]
  12. Longcope C., Bourget C., Flood C. The production and aromatization of dehydroepiandrosterone in post-menopausal women. Maturitas. 1982 Dec;4(4):325–332. doi: 10.1016/0378-5122(82)90065-2. [DOI] [PubMed] [Google Scholar]
  13. Longcope C. The metabolism of estrone sulfate in normal males. J Clin Endocrinol Metab. 1972 Jan;34(1):113–122. doi: 10.1210/jcem-34-1-113. [DOI] [PubMed] [Google Scholar]
  14. Longcope C., Williams K. I. The metabolism of estrogens in normal women after pulse injections of 3H-estradiol and 3H-estrone. J Clin Endocrinol Metab. 1974 Apr;38(4):602–607. doi: 10.1210/jcem-38-4-602. [DOI] [PubMed] [Google Scholar]
  15. Lønning E., Kvinnsland S., Bakke O. M. Effect of aminoglutethimide on antipyrine, theophylline, and digitoxin disposition in breast cancer. Clin Pharmacol Ther. 1984 Dec;36(6):796–802. doi: 10.1038/clpt.1984.259. [DOI] [PubMed] [Google Scholar]
  16. Lønning P. E., Kvinnsland S. Mechanisms of action of aminoglutethimide as endocrine therapy of breast cancer. Drugs. 1988 Jun;35(6):685–710. doi: 10.2165/00003495-198835060-00005. [DOI] [PubMed] [Google Scholar]
  17. Lønning P. E., Kvinnsland S., Thorsen T., Ueland P. M. Alterations in the metabolism of oestrogens during treatment with aminoglutethimide in breast cancer patients. Preliminary findings. Clin Pharmacokinet. 1987 Dec;13(6):393–406. doi: 10.2165/00003088-198713060-00004. [DOI] [PubMed] [Google Scholar]
  18. Lønning P. E., Ueland P. M., Kvinnsland S. The influence of a graded dose schedule of aminoglutethimide on the disposition of the optical enantiomers of warfarin in patients with breast cancer. Cancer Chemother Pharmacol. 1986;17(2):177–181. doi: 10.1007/BF00306750. [DOI] [PubMed] [Google Scholar]
  19. Newsome H. H., Brown P. W., Terz J. J., Lawrence W., Jr Medical and surgical adrenalectomy in patients with advanced breast carcinoma. Cancer. 1977 Feb;39(2):542–546. doi: 10.1002/1097-0142(197702)39:2<542::aid-cncr2820390224>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  20. Noel C. T., Reed M. J., Jacobs H. S., James V. H. The plasma concentration of oestrone sulphate in postmenopausal women: lack of diurnal variation, effect of ovariectomy, age and weight. J Steroid Biochem. 1981 Nov;14(11):1101–1105. doi: 10.1016/0022-4731(81)90039-x. [DOI] [PubMed] [Google Scholar]
  21. Reed M. J., Beranek P. A., Ghilchik M. W., James V. H. Estrogen production and metabolism in normal postmenopausal women and postmenopausal women with breast or endometrial cancer. Eur J Cancer Clin Oncol. 1986 Nov;22(11):1395–1400. doi: 10.1016/0277-5379(86)90151-3. [DOI] [PubMed] [Google Scholar]
  22. Roberts K. D., Rochefort J. G., Bleau G., Chapdelaine A. Plasma estrone sulfate levels in postmenopausal women. Steroids. 1980 Feb;35(2):179–187. doi: 10.1016/0039-128x(80)90101-4. [DOI] [PubMed] [Google Scholar]
  23. Samojlik E., Santen R. J., Wells S. A. Adrenal suppression with aminoglutethimide. II. Differential effects of aminoglutethimide on plasma androstenedione and estrogen levels. J Clin Endocrinol Metab. 1977 Sep;45(3):480–487. doi: 10.1210/jcem-45-3-480. [DOI] [PubMed] [Google Scholar]
  24. Santen R. J., Santner S., Davis B., Veldhuis J., Samojlik E., Ruby E. Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma. J Clin Endocrinol Metab. 1978 Dec;47(6):1257–1265. doi: 10.1210/jcem-47-6-1257. [DOI] [PubMed] [Google Scholar]
  25. Schanche J. S., Lønning P. E., Ueland P. M., Kvinnsland S. Determination of aminoglutethimide and N-acetylaminoglutethimide in human plasma by reversed-phase liquid chromatography. Ther Drug Monit. 1984;6(2):221–226. doi: 10.1097/00007691-198406000-00016. [DOI] [PubMed] [Google Scholar]
  26. Thompson E. A., Jr, Siiteri P. K. The involvement of human placental microsomal cytochrome P-450 in aromatization. J Biol Chem. 1974 Sep 10;249(17):5373–5378. [PubMed] [Google Scholar]
  27. Vermeulen A., Paridaens R., Heuson J. C. Effects of aminoglutethimide on adrenal steroid secretion. Clin Endocrinol (Oxf) 1983 Dec;19(6):673–682. doi: 10.1111/j.1365-2265.1983.tb00044.x. [DOI] [PubMed] [Google Scholar]
  28. Vermeulen A., Verdonck L. Sex hormone concentrations in post-menopausal women. Clin Endocrinol (Oxf) 1978 Jul;9(1):59–66. doi: 10.1111/j.1365-2265.1978.tb03572.x. [DOI] [PubMed] [Google Scholar]
  29. Wilkinson G. R., Shand D. G. Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther. 1975 Oct;18(4):377–390. doi: 10.1002/cpt1975184377. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES