Abstract
Daily administration of estrogen antagonists to premenopausal women has been incorporated into the adjuvant treatment of breast cancer. We have studied the changes in reproductive hormones, pituitary responses to hypothalamic-releasing hormones, and endometrial histology during treatment with the antiestrogen tamoxifen in five healthy, premenopausal women. These studies were carried out during one menstrual cycle before and during two cycles of antiestrogen treatment. All subjects continued to have regular menses with biphasic basal body temperature records. During treatment, estradiol (E2) levels were increased but followed the usual pattern reflecting follicular maturation and corpus luteum formation. The mean E2 concentration at the midcycle peak and during the luteal phase was twice that observed during the non-treatment cycle. By contrast, the concentrations and secretory patterns of luteinizing hormone and follicle-stimulating hormone were not greatly changed, and the gonadotropin responses to gonadotropin-releasing hormone were not suppressed.
Endometrial biopsies obtained during the follicular phase of control and tamoxifen treatment cycles showed no differences whereas biopsies obtained during the luteal phase of tamoxifen cycles uniformly showed a lack of changes attributed to progesterone action with no progression of histologic changes beyond those expected on day 7-8 of the luteal phase.
These observations are consistent with maturation of multiple ovarian follicles, a surprising finding considering the normal gonadotropin concentrations. The retarded development of the endometrium in the presence of supranormal serum E2 and progesterone concentrations is a morphologic demonstration of the antiprogestational effect of antiestrogens. The lack of gonadotropin suppression in the presence of hyperestrogenemia suggests a major antiestrogen action on the hypothalmus and pituitary gland.
Full text
PDF






Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Boyd A. E., 3rd, Sanchez-Franco F. Changes in the prolactin response to thyrotropin-releasing hormone (TRH) during the menstrual cycle of normal women. J Clin Endocrinol Metab. 1977 May;44(5):985–989. doi: 10.1210/jcem-44-5-985. [DOI] [PubMed] [Google Scholar]
- Cargille C. M., Rayford P. L. Characterization of antisera for human follicle-stimulating hormone radioimmunoassay. J Lab Clin Med. 1970 Jun;75(6):1030–1040. [PubMed] [Google Scholar]
- Clark J. H., Hardin J. W., Padykula H. A., Cardasis C. A. Role of estrogen receptor binding and transcriptional activity in the stimulation of hyperestrogenism and nuclear bodies. Proc Natl Acad Sci U S A. 1978 Jun;75(6):2781–2784. doi: 10.1073/pnas.75.6.2781. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clark J. H., Peck E. J., Jr, Anderson J. N. Oestrogen receptors and antagonism of steroid hormone action. Nature. 1974 Oct 4;251(5474):446–448. doi: 10.1038/251446a0. [DOI] [PubMed] [Google Scholar]
- Gore B. Z., Caldwell B. V., Speroff L. Estrogen-induced human luteolysis. J Clin Endocrinol Metab. 1973 Mar;36(3):615–617. doi: 10.1210/jcem-36-3-615. [DOI] [PubMed] [Google Scholar]
- Harman S. M., Louvet J. P., Ross G. T. Interaction of estrogen and gonadotrophins on follicular atresia. Endocrinology. 1975 May;96(5):1145–1152. doi: 10.1210/endo-96-5-1145. [DOI] [PubMed] [Google Scholar]
- Horwitz K. B., McGuire W. L. Estrogen control of progesterone receptor in human breast cancer. Correlation with nuclear processing of estrogen receptor. J Biol Chem. 1978 Apr 10;253(7):2223–2228. [PubMed] [Google Scholar]
- Horwitz K. B., McGuire W. L. Progesterone and progesterone receptors in experimental breast cancer. Cancer Res. 1977 Jun;37(6):1733–1738. [PubMed] [Google Scholar]
- Karsch F. J., Krey L. C., Weick R. F., Dierschke D. J., Knobil E. Functional luteolysis in the rhesus monkey; the role of estrogen. Endocrinology. 1973 Apr;92(4):1148–1152. doi: 10.1210/endo-92-4-1148. [DOI] [PubMed] [Google Scholar]
- Keye W. R., Jr, Jaffe R. B. Modulation of pituitary gonadotropin response to gonadotropin-releasing hormone by estradiol. J Clin Endocrinol Metab. 1974 May;38(5):805–810. doi: 10.1210/jcem-38-5-805. [DOI] [PubMed] [Google Scholar]
- Kiang D. T., Kennedy B. J. Tamoxifen (antiestrogen) therapy in advanced breast cancer. Ann Intern Med. 1977 Dec;87(6):687–690. doi: 10.7326/0003-4819-87-6-687. [DOI] [PubMed] [Google Scholar]
- Korenman S. G., Stevens R. H., Carpenter L. A., Robb M., Niswender G. D., Sherman B. M. Estradiol radioimmunoassay without chromatography: procedure, validation and normal values. J Clin Endocrinol Metab. 1974 Apr;38(4):718–720. doi: 10.1210/jcem-38-4-718. [DOI] [PubMed] [Google Scholar]
- Koseki Y., Zava D. T., Chamness G. C., McGuire W. L. Estrogen receptor translocation and replenishment by the antiestrogen tamoxifen. Endocrinology. 1977 Oct;101(4):1104–1110. doi: 10.1210/endo-101-4-1104. [DOI] [PubMed] [Google Scholar]
- Lehmann F., Just-Nastansky I., Behrendt B., Czygan P. J., Bettendorf G. Effect of post-ovulatory administered oestrogens on corpus luteum function. Acta Endocrinol (Copenh) 1975 Jun;79(2):329–336. doi: 10.1530/acta.0.0790329. [DOI] [PubMed] [Google Scholar]
- Lippman M., Bolan G., Huff K. The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res. 1976 Dec;36(12):4595–4601. [PubMed] [Google Scholar]
- Lunan C. B., Klopper A. Antioestrogens. A review. Clin Endocrinol (Oxf) 1975 Sep;4(5):551–572. doi: 10.1111/j.1365-2265.1975.tb01568.x. [DOI] [PubMed] [Google Scholar]
- Moseson D. L., Sasaki G. H., Kraybill W. G., Leung B. S., Davenport C. E., Fletcher W. S. The use of antiestrogens tamoxifen and nafoxidine in the treatment of human breast cancer in correlation with estrogen receptor values. A phase II study. Cancer. 1978 Mar;41(3):797–802. doi: 10.1002/1097-0142(197803)41:3<797::aid-cncr2820410303>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
- Odell W. D., Ross G. T., Rayford P. L. Radioimmunoassay for luteinizing hormone in human plasma or serum: physiological studies. J Clin Invest. 1967 Feb;46(2):248–255. doi: 10.1172/JCI105527. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rao B. R., Wiest W. G., Allen W. M. Progesterone "receptor" in rabbit uterus. I. Characterization and estradiol-17beta augmentation. Endocrinology. 1973 Apr;92(4):1229–1240. doi: 10.1210/endo-92-4-1229. [DOI] [PubMed] [Google Scholar]
- Ross G. T. Gonadotropins and preantral follicular maturation in women. Fertil Steril. 1974 Jun;25(6):522–543. doi: 10.1016/s0015-0282(16)40458-9. [DOI] [PubMed] [Google Scholar]
- Santen R. J., Leonard J. M., Sherins R. J., Gandy H. M., Paulsen C. A. Short- and long-term effects of clomiphene citrate on the pituitary-testicular axis. J Clin Endocrinol Metab. 1971 Dec;33(6):970–979. doi: 10.1210/jcem-33-6-970. [DOI] [PubMed] [Google Scholar]
- Sinha Y. N., Selby F. W., Lewis U. J., VanderLaan W. P. A homologous radioimmunoassay for human prolactin. J Clin Endocrinol Metab. 1973 Mar;36(3):509–516. doi: 10.1210/jcem-36-3-509. [DOI] [PubMed] [Google Scholar]
- Toft D., O'Malley B. W. Target tissue receptors for progesterone: the influence of estrogen treatment. Endocrinology. 1972 Apr;90(4):1041–1045. doi: 10.1210/endo-90-4-1041. [DOI] [PubMed] [Google Scholar]
- UTIGER R. D. RADIOIMMUNOASSAY OF HUMAN PLASMA THYROTROPIN. J Clin Invest. 1965 Aug;44:1277–1286. doi: 10.1172/JCI105234. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vandenberg G., Yen S. S. Effect of anti-estrogenic action of clomiphene during the menstrual cycle: evidence for a change in the feedback sensitivity. J Clin Endocrinol Metab. 1973 Sep;37(3):356–365. doi: 10.1210/jcem-37-3-356. [DOI] [PubMed] [Google Scholar]
- Vekemans M., Robyn C. The influence of exogenous estrogen on the circadian periodicity of circulating prolactin in women. J Clin Endocrinol Metab. 1975 May;40(5):886–889. doi: 10.1210/jcem-40-5-886. [DOI] [PubMed] [Google Scholar]
- Wang C. F., Yen S. S. Direct evidence of estrogen modulation of pituitary sensitivity to luteinizing hormone-releasing factor during the menstrual cycle. J Clin Invest. 1975 Jan;55(1):201–204. doi: 10.1172/JCI107913. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wise A. J., Gross M. A., Schalch D. S. Quantitative relationships of the pituitary-gonadal axis in postmenopausal women. J Lab Clin Med. 1973 Jan;81(1):28–36. [PubMed] [Google Scholar]
- Yen S. S., Vandenberg G., Siler T. M. Modulation of pituitary responsiveness to LRF by estrogen. J Clin Endocrinol Metab. 1974 Jul;39(1):170–177. doi: 10.1210/jcem-39-1-170. [DOI] [PubMed] [Google Scholar]