Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 1990 Oct;62(4):679–683. doi: 10.1038/bjc.1990.356

The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer.

R C Stein 1, M Dowsett 1, A Hedley 1, J C Gazet 1, H T Ford 1, R C Coombes 1
PMCID: PMC1971476  PMID: 2145964

Abstract

The aromatase inhibitor, 4-hydroxyandrostenedione (4OHA) is an effective treatment for advanced post-menopausal breast cancer. The clinical and endocrine effects of 4OHA treatment were studied in five pre- and perimenopausal women with metastatic breast cancer. Serum oestradiol levels were not significantly reduced as a result of treatment with 500 mg of 4OHA by weekly i.m. injections and no patient had a tumour response. Four patients were subsequently treated with the luteinising hormone releasing hormone (LHRH) analogue, gosereline, and three had objective responses. The endocrine effects of combined treatment with goserelin (Zoladex), and 4OHA were studied in a further five premenopausal women. Serum oestradiol levels after treatment with goserelin alone were typical of post-menopausal women. Addition of 4OHA led to a further suppression of oestradiol to within the range observed in post-menopausal patients treated with further suppression of oestradiol to within the range observed in post-menopausal patients treated with 4OHA. Six patients whose tumours had regressed as a result of goserelin treatment and who subsequently relapsed were then given combined treatment. Four of the six experienced a second remission. We conclude that while 4OHA alone is unlikely to be a satisfactory treatment for premenopausal patients with advanced breast cancer, 4OHA in conjunction with goserelin leads to profound suppression of oestradiol. The combination of LHRH analogue and aromatase inhibitor may prove to be a superior treatment to LHRH analogue alone in these patients.

Full text

PDF

Selected References

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

  1. Brodie A. M., Hammond J. O., Ghosh M., Meyer K., Albrecht E. D. Effect of treatment with aromatase inhibitor 4-hydroxandrostenedione on the nonhuman primate menstrual cycle. Cancer Res. 1989 Sep 1;49(17):4780–4784. [PubMed] [Google Scholar]
  2. Coombes R. C., Goss P., Dowsett M., Gazet J. C., Brodie A. 4-Hydroxyandrostenedione in treatment of postmenopausal patients with advanced breast cancer. Lancet. 1984 Dec 1;2(8414):1237–1239. doi: 10.1016/s0140-6736(84)92795-8. [DOI] [PubMed] [Google Scholar]
  3. Dowsett M., Cantwell B., Lal A., Jeffcoate S. L., Harris A. L. Suppression of postmenopausal ovarian steroidogenesis with the luteinizing hormone-releasing hormone agonist goserelin. J Clin Endocrinol Metab. 1988 Apr;66(4):672–677. doi: 10.1210/jcem-66-4-672. [DOI] [PubMed] [Google Scholar]
  4. Dowsett M., Cunningham D. C., Stein R. C., Evans S., Dehennin L., Hedley A., Coombes R. C. Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients. Cancer Res. 1989 Mar 1;49(5):1306–1312. [PubMed] [Google Scholar]
  5. Dowsett M., Goss P. E., Powles T. J., Hutchinson G., Brodie A. M., Jeffcoate S. L., Coombes R. C. Use of the aromatase inhibitor 4-hydroxyandrostenedione in postmenopausal breast cancer: optimization of therapeutic dose and route. Cancer Res. 1987 Apr 1;47(7):1957–1961. [PubMed] [Google Scholar]
  6. Dutta A. S., Furr B. J., Giles M. B., Valcaccia B., Walpole A. L. Potent agonist and antagonist analogues of luliberin containing an azaglycine residue in position 10. Biochem Biophys Res Commun. 1978 Mar 30;81(2):382–390. doi: 10.1016/0006-291x(78)91544-9. [DOI] [PubMed] [Google Scholar]
  7. Ferguson K. M., Hayes M., Jeffcoate S. L. A standardised multicentre procedure for plasma gonadotrophin radioimmunoassay. Ann Clin Biochem. 1982 Sep;19(Pt 5):358–361. doi: 10.1177/000456328201900507. [DOI] [PubMed] [Google Scholar]
  8. Goss P. E., Powles T. J., Dowsett M., Hutchison G., Brodie A. M., Gazet J. C., Coombes R. C. Treatment of advanced postmenopausal breast cancer with an aromatase inhibitor, 4-hydroxyandrostenedione: phase II report. Cancer Res. 1986 Sep;46(9):4823–4826. [PubMed] [Google Scholar]
  9. Harris A. L., Dowsett M., Jeffcoate S. L., McKinna J. A., Morgan M., Smith I. E. Endocrine and therapeutic effects of aminoglutethimide in premenopausal patients with breast cancer. J Clin Endocrinol Metab. 1982 Oct;55(4):718–722. doi: 10.1210/jcem-55-4-718. [DOI] [PubMed] [Google Scholar]
  10. Hayward J. L., Carbone P. P., Heuson J. C., Kumaoka S., Segaloff A., Rubens R. D. Assessment of response to therapy in advanced breast cancer: a project of the Programme on Clinical Oncology of the International Union Against Cancer, Geneva, Switzerland. Cancer. 1977 Mar;39(3):1289–1294. doi: 10.1002/1097-0142(197703)39:3<1289::aid-cncr2820390340>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  11. Hemsell D. L., Grodin J. M., Brenner P. F., Siiteri P. K., MacDonald P. C. Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab. 1974 Mar;38(3):476–479. doi: 10.1210/jcem-38-3-476. [DOI] [PubMed] [Google Scholar]
  12. Klijn J. G., de Jong F. H. Treatment with a luteinising-hormone-releasing-hormone analogue (buserelin) in premenopausal patients with metastatic breast cancer. Lancet. 1982 May 29;1(8283):1213–1216. doi: 10.1016/s0140-6736(82)92339-x. [DOI] [PubMed] [Google Scholar]
  13. Koos R. D., LeMaire W. J., Hung T. T., Brodie A. M. Comparison of the effect of 4-hydroxy-4-androstene-3,17-dione on aromatase activity in granulosa cells from preovulatory follicles of rats, rabbits, and humans. Steroids. 1985 Feb;45(2):143–150. doi: 10.1016/0039-128x(85)90043-1. [DOI] [PubMed] [Google Scholar]
  14. Mendelson C. R., Simpson E. R. Regulation of estrogen biosynthesis by human adipose cells in vitro. Mol Cell Endocrinol. 1987 Aug;52(3):169–176. doi: 10.1016/0303-7207(87)90041-4. [DOI] [PubMed] [Google Scholar]
  15. Nicholson R. I., Walker K. J., Turkes A., Turkes A. O., Dyas J., Blamey R. W., Campbell F. C., Robinson M. R., Griffiths K. Therapeutic significance and the mechanism of action of the LH-RH agonist ICI 118630 in breast and prostate cancer. J Steroid Biochem. 1984 Jan;20(1):129–135. doi: 10.1016/0022-4731(84)90199-7. [DOI] [PubMed] [Google Scholar]
  16. Reed M. J., Owen A. M., Lai L. C., Coldham N. G., Ghilchik M. W., Shaikh N. A., James V. H. In situ oestrone synthesis in normal breast and breast tumour tissues: effect of treatment with 4-hydroxyandrostenedione. Int J Cancer. 1989 Aug 15;44(2):233–237. doi: 10.1002/ijc.2910440208. [DOI] [PubMed] [Google Scholar]
  17. Santen R. J., Samojlik E., Wells S. A. Resistance of the ovary to blockade of aromatization with aminoglutethimide. J Clin Endocrinol Metab. 1980 Sep;51(3):473–477. doi: 10.1210/jcem-51-3-473. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Sherman B. M., West J. H., Korenman S. G. The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Metab. 1976 Apr;42(4):629–636. doi: 10.1210/jcem-42-4-629. [DOI] [PubMed] [Google Scholar]
  20. Silva M. C., Rowlands M. G., Dowsett M., Gusterson B., McKinna J. A., Fryatt I., Coombes R. C. Intratumoral aromatase as a prognostic factor in human breast carcinoma. Cancer Res. 1989 May 15;49(10):2588–2591. [PubMed] [Google Scholar]
  21. Smith I. E., Fitzharris B. M., McKinna J. A., Fahmy D. R., Nash A. G., Neville A. M., Gazet J. C., Ford H. T., Powles T. J. Aminoglutethimide in treatment of metastatic breast carcinoma. Lancet. 1978 Sep 23;2(8091):646–649. doi: 10.1016/s0140-6736(78)92759-9. [DOI] [PubMed] [Google Scholar]
  22. Wander H. E., Blossey H. C., Nagel G. A. Aminoglutethimide in the treatment of premenopausal patients with metastatic breast cancer. Eur J Cancer Clin Oncol. 1986 Nov;22(11):1371–1374. doi: 10.1016/0277-5379(86)90147-1. [DOI] [PubMed] [Google Scholar]
  23. Williams M. R., Walker K. J., Turkes A., Blamey R. W., Nicholson R. I. The use of an LH-RH agonist (ICI 118630, Zoladex) in advanced premenopausal breast cancer. Br J Cancer. 1986 May;53(5):629–636. doi: 10.1038/bjc.1986.106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wing L. Y., Garrett W. M., Brodie A. M. Effects of aromatase inhibitors, aminoglutethimide, and 4-hydroxyandrostenedione on cyclic rats and rats with 7,12-dimethylbenz(a)anthracene-induced mammary tumors. Cancer Res. 1985 Jun;45(6):2425–2428. [PubMed] [Google Scholar]
  25. Wing L. Y., Hammond J. O., Brodie A. M. Differential responses of sex steroid target tissues of rats treated with 4-hydroxyandrostenedione. Endocrinology. 1988 Jun;122(6):2418–2427. doi: 10.1210/endo-122-6-2418. [DOI] [PubMed] [Google Scholar]

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

RESOURCES