Tamoxifen and Ovarian Function

Background

Some studies suggest that the clinical parameter “amenorrhea” is insufficient to define the menopausal status of women treated with chemotherapy or tamoxifen. In this study, we investigated and compared the ovarian function defined either by clinical or biological parameters in pre-menopausal breast cancer patients treated with tamoxifen administered as adjuvant therapy.

Materials and Methods

Between 1999 and 2003, 138 premenopausal patients consecutively treated for early breast cancer were included. Sixty-eight received tamoxifen in monotherapy as the only adjuvant systemic treatment (Group I) and 70 were treated with tamoxifen after adjuvant chemotherapy (Group II). All patients had a confirmed premenopausal status based on clinical parameters and hormonal values at study entry. They were followed prospectively every 3 months for 3 years: menses data, physical examination and blood tests (LH, FSH, 17-beta-estradiol). Vaginal ultrasonography was carried out every 6 months. After 3 years, prospective evaluation was completed and monitoring of ovarian function was performed as usual in our institution (1x/year). All data were retrospectively evaluated in 2011.

Results

Three patients were excluded from the study in group I and 2 were excluded in group II. Patients were divided into 4 subgroups according to clinical data, i.e. menses patterns. These patterns were assessed by questionnaires. a: Regular menses (>10 cycles/year) b: Oligomenorrhea (5 to 9 cycles/year) c: Severe oligomenorrhea (1 to 4 cycles/year) d: Complete amenorrhea Estrogen levels did not appear to have any impact on disease-free survival rates after 3 or 8 years. FSH values were also documented and analyzed. They exhibited the same profile as estradiol values.

Conclusions

Amenorrhea is an insufficient parameter to define menopausal status in patients receiving tamoxifen. Low estradiol levels must be coupled with other biological parameters to characterize endocrine status. These data are very important for the choice of endocrine therapy.     

Carcinosarcoma of the uterus. Cytologic and ultrastructural features

A 56-year-old woman presented with a carcinosarcoma consisting of a small focus of adenocarcinoma and a larger endometrial stromal sarcoma component. Although a preoperative endometrial biopsy revealed only adenocarcinoma, an endometrial smear obtained with an endometrial brush sampler revealed many undifferentiated malignant cells and a smaller number of adenocarcinoma cells. These undifferentiated malignant cells were cytologically identical to the stromal sarcoma cells in an imprint smear from the surgically removed tumor. The cellular and ultrastructural features of the stromal sarcoma are described in detail.     

Progesterone in the uterus. IV. Dependence of the in vitro progesterone metabolism in the rat uterus on the progesterone concentration.

After incubation of uterine segments of normal rats with various 3H-progesterone concentrations in nutrient medium, different patterns of radioactive steroids were obtained in uterine tissue. Using hormone concentrations of less than 5 X 10(-7)M progesterone metabolites could not be detected in the tissue. A series of metabolites appeared with progesterone concentrations of 10(-6)M and higher. Six radiometabolites were identified and two were characterized.     

Progesterone in the uterus. V. Correlation of the in vitro progesterone metabolism with the progesterone binding in rat uterus.

Incubations of rat uterine segments with varying 3H-progesterone concentrations were performed to study the hormone uptake by the tissue. The radioactivity of the uterus and the nutrient medium were plotted in form of a SCATCHARD plot. Additionally, the binding capacity of the uterine cytosol was measured. In both systems, the hormone was found to be associated with two components which differ from each other in their association constants. The progesterone metabolism occuring at a hormone concentration of 10(-6)M and more in the incubation medium is discussed with respect to the affinity and the capacity of the hormone binding components.     

Actin from pig and rat uterus.

Smooth-muscle actin was isolated from pig uterus and from pregnant-rat uterus. Methods involving acetone-dried powders were unsuccessful, and a column-chromatographic procedure was developed, with proteinase inhibitors and avoiding polymerization as a purification step. The yield of pure actin was 0.8--1.5 mg/g wet wt. of uterus, which should be compared with an expected yield of actin from skeletal muscle of 2--4 mg/g wet wt. The actin was pure as judged by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, and exhibited alpha-, beta-, and gamma-forms on isoelectric focusing. It possessed a blocked N-terminal amino acid residue, and its amino acid analysis conformed to those of other actins. The rat uterine actin was available only in small amounts (5--10 mg) and did not polymerize. The pig uterine actin could be obtained in amounts up to 30 mg, polymerized reversibly, and activated a skeletal myosin Mg2+-dependent ATPase.     

Tamoxifen prevents bone loss in castrated male mice.

The selective estrogen receptor modulator tamoxifen was administered to intact and castrated male mice, and its effects on tibial bones and circulatory calcium, phosphate and testosterone were compared with controls and castrated animals. Tamoxifen in a dose used in humans for treatment of breast cancer decreased the weight of seminal vesicles, an organ which is highly sensitive to the androgenic effect, decreased the concentration of testosterone, but did not have any negative effect on bone density or mineral content in intact mice. When castrated mice with extraordinarily low concentrations of testosterone and weights of seminal vesicles were treated with tamoxifen, the changes in bone density and bone mineral resulting from castration were not only entirely prevented, but increased above the values of intact mice. At the same time, cortical bone was lost in orchidectomized mice, and this decrease in cortical thickness of femur was completely prevented by tamoxifen treatment. Pharmacological therapy with estrogen agonist on bone, tamoxifen in androgen deficient adult male mice prevents bone loss.     

Progesterone in the uterus. X. Dependence of the in vitro progesterone metabolism on progesterone binding in rat uterus

The effect of estrogen pretreatment was stud-ed on the in vitro metabolism and binding of progesterone in uteri of ovariectomized rats in order to prove the dependence of the metabolism of progesterone on its binding. For this purpose, the extent of progesterone binding was varied in uterine tissue by different estrogen treatment of the rats and compared with the metabolism under the same conditions. The protein content determined in 100 mg tissue was used as parameter indicating the success of the pretreatment. Estrogen exposure of the rats for 30 or 45 hrs. caused a rise of protein amount in uterine tissue which was accompanied by an increase of binding sites of progesterone binding components. The binding sites were determined by charcoal adsorption technique and SCATCHARD-analysis. Under nearly the same success of estrogen pretreatment, the increase of the portein amount and with it the rise of binding sites reduced the amount of progesterone metabolites in uterine tissue. The metabolites were determined by quantitative TLC-analysis of the recovered compounds from uterine segments after incubation with radioactive progesterone. Additionally, an enlarged metabolic rate could be observed after saturation of binding components. It is concluded from the results of these experiments that progesterone binding components are factors limiting the enzymatic conversion of progesterone in rat uterus.