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.