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Endometrial estrogen and progestin receptors were quantitatively measured in the cytosol (ERc, PRc) and nuclear (ERn, PRn) fractions, the activity of 17 beta-hydroxysteroid dehydrogenase measured in 13 normal women in the late proliferative phase of the cycle (control group), in 33 patients with adenocarcinoma, and in 6 patients with other malignancies of the endometrium. The parameters measured had relatively small variations in the control group, whereas the opposite was true for the malignant endometrium. ERc and PRc were present in significantly higher concentrations in normal endometrial tissue (167 and 1697 fmol/mg cytosol protein, respectively) than in malignant endometrial tissue (45 and 116 fmol/mg cytosol protein, respectively), and the ratios of ERc/ERn and PRc/PRn were higher (P much less than .001 in both cases) in the normal group. The activities of 17 beta-hydroxysteroid dehydrogenase were identical in normal and adenocarcinoma tissue and correlated with PRc in carcinomatous endometrium. The present results support previous findings that the great majority of endometrial adenocarcinoma specimens have significant concentrations of ERc and PRc and that these concentrations are lower than in normal endometrium. In addition, they demonstrate that nuclear location of the female sex steroid receptors is favored in the malignant tissue. Despite these differences, the 17 beta-hydroxysteroid dehydrogenase activities were identical in proliferative endometrium and in endometrial adenocarcinoma.

Steroid hormone receptors provide the means by which estrogen and progesterone influence their target tissues. Receptor assays have proved clinically useful in the management of breast cancer, and current research indicates they may be valuable in managing some gynecologic neoplasms. This is a review of the current and potential importance of receptors in gynecologic oncology.

The estrogen receptor content, determined immunohistochemically by staining with monoclonal antibodies, was studied in seven consecutive cases of endometrial stromal sarcoma. In addition, the mitotic rate and immunohistochemical patterns (vimentin, desmin, actin, cytokeratins) were determined. Five of seven cases contained estrogen receptors, three low-grade (fewer than 10 mitoses/10 high-power fields [hpf]) and two high-grade (10 or more mitoses/10 hpf), the latter having a relatively low mitotic rate. The two negative cases were high-grade with a very high number of mitoses. Tumor cells were positive only to vimentin. Based on these results, we postulate that estrogen receptors are undetectable only in highly proliferating neoplasms. Thus, immunohistochemically determined estrogen receptor levels may indicate the aggressiveness of endometrial stromal sarcoma, and might be a guideline in selecting patients for hormonal therapy. The presence of positive immunostaining to vimentin confirms the mesenchymal origin of endometrial stromal sarcoma.

Estrogen and progesterone receptors were measured in tissues from 43 patients with various uterine sarcomas using the dextran-coated charcoal assay. Estrogen receptor was present in 55.5% and progesterone receptor in 55.8% of samples, at median estrogen and progesterone receptor concentrations of 10.7 and 15.8 fmol/mg cytosol protein, respectively. These median values are much lower than those in 30 consecutive endometrial adenocarcinomas and 50 breast carcinomas assayed in our laboratory. Progesterone receptor status correlated strongly with estrogen receptor status in uterine sarcomas (P = .001). Estrogen and progesterone receptor levels were not influenced by stage, grade, or mitotic count. Patients 50 years of age or less had significantly higher progesterone receptor than those over 50. No such age effect was seen for estrogen receptor. Endometrial stromal sarcoma had higher estrogen and progesterone receptor levels than other histologic types. Low-grade endometrial stromal sarcomas had higher median estrogen receptors (238.9 fmol/mg) and better survival (all patients alive at 6-12 months) than did high grade (N = 7) endometrial stromal sarcomas (median ER = 6.6 fmol/mg, all dead of disease at 8-27 months). For all histologic types, evaluable patients with stage I or II disease (N = 16) were more likely to survive longer than one year than those with stage III or IV disease (N = 13, P = .003). Evaluable patients with estrogen receptor-positive sarcomas were more likely to survive longer than one year than those with estrogen receptor-negative tumors (P = .006). With one exception, an endometrial stromal sarcoma, hormonal therapy exerted no beneficial effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Three hundred forty-nine cases of primary endometrial carcinoma (endometrioid, adenosquamous, and clear-cell) were studied to investigate the relative prognostic importance of age, menopausal status, stage, histology, myometrial invasion, and estrogen and progesterone receptor content. Excluding menopausal status, all of these variables had a significant relationship to overall survival in a univariate analysis. Using a Cox multivariate regression analysis, stage, age, and an estrogen receptor value of more than 70 fmol/mg protein, combined with a progesterone receptor value of more than 30 fmol/mg protein, were independently associated with survival. The results demonstrate that for maximum prognostic information, both estrogen and progesterone content of tumors should be measured. Maximum prognostic information is obtained by using cutoff levels that are much higher than those traditionally accepted. This has particular relevance for patient stratification in clinical trials investigating receptor information and response to adjuvant or therapeutic treatment.

Seventy-eight endometrial carcinoma specimens from 74 patients were evaluated for estrogen (E2R) and progesterone (PrR) receptors by multiconcentration saturation and sucrose density gradient analysis. The clinical stage and histologic grade of the tumors and the patients' clinical course were compared to the qualitative and quantitative evaluations of E2R and PrR. Although no correlation was seen between receptor content and extent of disease, tumors with significant levels of E2R and PrR tended to be less aggressive than those in which neither receptor was detected. The histologic grade correlated with a combination of estrogen and progesterone receptor content. In 92% of the patients there was a concordance between the presence or absence of E2R and PrR in the tumor and a clinical response to progestin therapy. The significance of these findings in relationship to the presence of multiple forms of steroid binding is discussed.

Tissue proteins in paired samples of uterine leiomyomas and normal myometria from 26 patients were compared after extraction with 9 M urea, separation by two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), and visualization by silver staining. A creatine kinase carbamylation train and a rat heart extract were used as internal standards for the relative charge and the relative molecular weight (Mr) scales, respectively. Two groups of four proteins each, a first group of Mr = 34,500 (34K) and relative charge of creatine kinase of -14 to -21(P34a-d) and a second group of Mr = 56,000 (56K) and relative charge of creatine kinase less than -23(P56a-d), were more frequently expressed in uterine leiomyoma tissue than in normal myometrial tissue: P34, 14 of 26 (53.8%) in tumors and zero of 26 (0%) in normal myometria; P56a&d, 17 of 26 (65.3%); P56b&c, 20 of 26 (76.9%) in tumors and P56a&d, zero of 26 (0%); and P56b&c, 12 of 26 (46.1%) in normal myometria. Both P34 and P56 were expressed more frequently in the uterine leiomyoma during the proliferative phase than during the nonproliferative phase (P34 in proliferative phase: 12 of 13, 92.3%; and in nonproliferative phase: two of 13, 15.3%; P56a-d in proliferative phase: 13 of 13, 100%; and in nonproliferative phase: P56a&d, four of 13, 30.7%, and P56b&c, seven of 13, 53.8%). The cyclic expression of P34 and P56 suggests that their synthesis is related to the intrinsic hormonal environment of the tumors.

Eighty-six cases of primary endometrial carcinoma were assayed for the presence or absence of cytoplasmic estrogen and progesterone receptors by the saturation point dextran-coated charcoal assay. The levels of cytoplasmic progesterone receptors and estrogen receptors were analyzed according to clinical stage, histologic type and grade of the tumor, presence or absence of lymph node metastases, myometrial invasion, and survival. The cases were divided into positive and negative receptor groups with levels chosen of greater than 10 fmol/mg of cytosol protein for progesterone receptor and 5 fmol/mg of cytosol protein for estrogen receptor as discrimination points. Statistically significant survival differences were found between estrogen receptor positive versus estrogen receptor negative patients, progesterone receptor positive versus progesterone receptor negative patients, and estrogen positive-progesterone receptor positive versus estrogen negative-progesterone receptor negative patients. Mean cytoplasmic estrogen and progesterone receptor levels were inversely proportional to grade. This report suggests that treatment protocols should be devised to reflect the prognostic significance of receptor status.

The presence of an estrogen-regulated protein of Mr 24,000 (24K) was studied in 43 patients diagnosed as having endometrial adenocarcinoma. using an anti-24K monoclonal antibody, a modified immunoperoxidase system (avidinbiotin complex) was used to detect the presence of 24K in formalin-fixed, paraffin-embedded tissue samples. The positivity for 24K was correlated with low tumor histologic grade, few mitotic figures, few nucleoli, and a low degree of nuclear pleomorphism. These data suggest that 24K may be a potential marker of tumor differentiation.

Progesterone and estrogen receptor localization, using monoclonal anti-receptor antibodies JZB39 and H222, was studied in 105 endometrial adenocarcinomas. Immunohistochemical evaluation incorporated both intensity and distribution of staining. Both anti-progesterone receptor and anti-estrogen receptor localized in the nucleus of target cells. Significant levels of progesterone receptor and estrogen receptor were seen localized in stromal and myometrial elements that diverged from the malignant epithelial component. Analyses of endometrial adenocarcinomas with anti-progesterone receptor and anti-estrogen receptor antibodies correlated with histologic differentiation. The ability to define divergent receptor populations in stromal and myometrial elements versus malignant epithelial elements indicates that immunohistochemical assay of progesterone and estrogen receptor provides information complementary to that from conventional quantitative ligand binding assays.