Edle Utaaker

Steroid receptor content in human ovarian tumors: survival of patients with ovarian carcinoma related to steroid receptor content

Steroid receptors were measured in 31 malignant and 29 benign or semimalignant ovarian tumors in a prospective study. Estrogen receptors (ER) were found more often in highly differentiated malignant tumors (86%) than in poorly differentiated ones (23%). No such difference was found for progesterone receptor (PR). Receptor content was not related to clinical stage. The median survival of patients with PR+ or ER+/PR+ malignant tumors was 30 and 31.5 months, respectively, compared to 10 and 9 months for those with receptor negative tumors. This positive prognostic information could not be demonstrated for ER alone. Receptor content and distribution were similar in benign and semimalignant tumors. Measurement of hormone receptors in ovarian cancers can thus give valuable prognostic information.

DNA ploidy and steroid receptors as predictors of disease course in patients with endometrial carcinoma

Prognostic factors for outcome of malignant disease should be based on objective assessments whenever possible, so that the results may be reproduced. In a prospective study, tumor samples from 75 patients were subjected to flow cytometric DNA analysis. Samples were also taken from 61 patients for estradiol and progesterone receptor measurements. The course of the disease was analysed with regard to ploidy and receptor status. Receptor status was significantly correlated with ploidy, as diploid tumors were more often receptor‐positive or receptor‐rich (≥30 fmo/mg protein). Mortality and recurrence rates were highest among patients with aneuploid or receptor‐poor tumors. Ploidy, receptor status, histological grade, surgical stage, and myometrial invasion were found to be of significant prognostic value. By multivariate analysis, ploidy was indicated to be the best predictor, followed by surgical stage. DNA and receptor measurements are recommended in research on endometrial carcinoma, and may become useful in routine clinical work.

The distribution and prognostic implications of steroid receptors in endometrial carcinomas.

Estradiol receptors (ER) were measured in 71 and progesterone receptors (PR) in 62 primary endometrial carcinomas. ER were found in 62 (87%) and PR in 56 (90%) of the tumors. Fifty-six tumors were ER+/PR+ and 4 were ER-/PR-. The frequency of receptor positive tumors was not significantly correlated to histological grade. Highly differentiated tumors were, however, more often ER and PR rich (greater than or equal to 30 fmole/mg protein) as compared to poorly differentiated tumors. The median ER and PR values for grade I tumors were also significantly higher than for grade III tumors. No significant differences were found in the frequency of patients with ER or PR rich tumors in the different FIGO or surgical stages. The receptor status was not related to depth of myometrial infiltration. Recurrence rates and death rates were significantly higher in patients with PR poor as compared to those with PR rich tumors. This prognostic information could not be shown for ER.

Influence of progestins on serum hormone levels in postmenopausal women with advanced breast cancer-I. general findings

The influence of oral high dose progestin (medroxyprogesterone acetate, MPA and megestrol acetate, MA) treatment on serum hormone levels was studied in ten postmenopausal women with advanced breast cancer. The gonadotropins and ACTH were significantly reduced by greater than 50 and 23%, respectively. Serum cortisol, DHEAS, androstenedione and testosterone were all significantly reduced (mean reduction between 64 and 76%), while serum estrone, estradiol and estrone sulfate were significantly reduced by 20-30%. Sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CGB) were reduced by 68 and 25%, respectively. Although the dose of MA used (160 mg/day) was only 1/6 of the MPA dose (1000 mg/day), the mean serum level of MA was 2-fold higher than the mean serum level of MPA. MPA treatment gave a more pronounced suppression of SHBG than MA treatment, while estrone sulfate levels were more suppressed by MA. These findings suggest a differential effect of MPA and MA on certain plasma hormones, possibly of importance for understanding the mechanism of action of the two drugs. The reduction of estrone sulfate may be beneficial for the action of MA against breast cancer.

Oestrone sulphatase activity of the rat uterus in different hormonal states.

Oestrone sulphatase activity was determined in 12,500 g supernatant of rat homogenates. The conditions used were 0.5 mM oestrone sulphate and 30 min incubation at pH 8.0 and 37 degrees C. The enzyme activity in uteri from normal animals was found to be 5.1 +/- 0.7 nmol (mg protein)-1 h-1. In ovariectomized and hypophysectomized animals the values were significantly higher, whereas subcutaneous administration of 17 beta-oestradiol to such rats resulted in significantly decreased oestrone sulphatase activities. Progesterone increased the enzyme activity of intact rats. It is concluded that the uterine tissue of rats contains oestrone sulphatase which may be of biological importance and which is inhibited by oestrogen.

Pharmacokinetics and metabolism of medroxyprogesterone acetate in patients with advanced breast cancer

The pharmacokinetics and metabolism of medroxyprogesterone acetate (MPA) were studied in patients with advanced breast cancer after i.v. injection and oral administration of [3H]MPA. MPA was distributed very rapidly into three compartments after i.v. injections, revealing half-lives of 4-7 h. Using a nonlinear model fitting metabolic clearance rates (MCR) were found to be 652 1/day before and 601 1/day during MPA treatment, and distribution volumes (V0) 5.9 and 3.41 respectively. The major metabolite of MPA following i.v. injection was a glucuronide of MPA, presumably of the 3-enol form. After oral administration the radioactivity in serum increased rapidly and reached a plateau of about 1% of the dose per litre serum after approx 2 h. About 80-90% of the radioactivity was found in the water phase after hexane extraction, persumably as glucuronides of metabolites more polar than MPA. Radioimmunoassay (RIA) of MPA in untreated serum samples showed 3-8-fold greater MPA values as compared to measurements in hexane extracts of serum. Ethanol extraction did not remove these interfering substances. Extraction of serum with a low polar solvent before RIA of MPA is essential in order to prevent great overestimation, as the glucuronidated polar metabolites most likely will crossreact in an assay with an antiserum raised against a MPA-3-O-carboximethyloxime coupled to bovine serum albumin.

Effect of oral high-dose progestins on the disposition of antipyrine, digitoxin, and warfarin in patients with advanced breast cancer

SummaryThe influence of two progestins, medroxyprogesterone acetate (MPA) and megestrol acetate (MA), given orally in high doses, on the pharmacokinetics of antipyrine, digitoxin, and warfarin were studied in patients with advanced breast cancer. Antipyrine and warfarin were given as a single test dose before and after 5 weeks of progestin treatment. The pharmacokinetics of digitoxin was investigated at steady state in patients receiving this drug therapeutically before and during treatment with progestins. Small changes in clearance rates for antipyrine, warfarin, and digitoxin were found. A minor decrease observed in warfarin clearance however may be of clinical importance. Half-lives decreased by 13% for antipyrine and increased by 71% for warfarin. High-dose progestins given orally do not seem to have a major influence on drug metabolism, probably reflecting a minor effect on drug and steroid-metabolizing microsomal mono-oxygenases in the liver.

Steroid receptors in human endometrium. comparison of data obtained by three different methods

To find a method for steroid receptor measurement in small endometrial tissue samples (less than 100 mg), an isoelectric focusing assay has been compared with a dextran-coated charcoal assay for oestradiol receptor. The results correlated well (r = 0.85) and this indicates that isoelectric focusing is a good technique for oestradiol receptor determination. Te isoelectric focusing of progesterone receptor has been compared with a dextran-coated charcoal assay and sucrose density gradient centrifugation. Isoelectric focusing gave recoveries of 0-26% compared to receptor values obtained with the two other methods, which correlated well (r = 0.97). The low recovery implies that the isoelectric focusing assay is not suitable for progesterone receptor determination.