The pattern of estradiol and progesterone differs in serum and tissue of benign and malignant ovarian tumors.

Epidemiological studies have indicated a relationship between gonadal steroid hormones and ovarian cancer. A production of both estradiol and progesterone by ovarian cancers has been demonstrated. The local steroid concentrations and the putative relation to histopathological and clinical condition were investigated herein. Ovarian tissue, ovarian tumor cyst fluid, ovarian vein samples and peripheral serum concentrations of estradiol and progesterone in pre- and post-menopausal women, subdivided into groups with normal ovaries, benign, borderline and malignant ovarian tumors, were quantitatively assessed. Both ovarian tissue concentrations of estradiol and progesterone were more than 100-fold higher than in serum. Based on differences in concentrations between different ovarian tumor groups, the data is not coherent with the previously suggested increased production of estradiol and progesterone in ovarian cancer tissue, since post-menopausal women with ovarian cancer presented lower median tissue hormone levels, most pronounced between malignant and benign tumors; median (25 and 75 percentile) estradiol; 9.40 (6.67-15.50) vs 16.44 (12.49-23.20), p=0.02 and progesterone; 308 (240-575) vs 957 (553-1143) pmol/g wet weight, p<0.01, n=81. Lower concentrations of estradiol, but not progesterone, were found in ovarian cancer tissue, ovarian cyst fluid and peripheral serum in patients with FIGO stages 3 and 4 than in stages 1 and 2. The novel finding of a large ovarian tissue to serum difference of both estradiol and progesterone indicates an important role of ovarian tissue concentrations in tumor biology and raises the question of adequate doses of anti-hormonal therapy in women with ovarian cancer.

Steroid receptors and hormones in relation to cell proliferation and apoptosis in poorly differentiated epithelial ovarian tumors.

The purpose of this study was to further investigate the role of estrogen but especially progesterone on epithelial ovarian tumor development since previous studies have suggested a relationship between serum progesterone, progesterone receptor expression and prognosis. Serum progesterone concentration, the immunohistochemical expression of estrogen receptor alpha (ER), progesterone receptor A/B (PR), Ki-67, Bcl-2, p53, apoptosis and morphology were determined in 33 patients, all with poorly differentiated surface epithelial ovarian tumors of different types. ER was expressed in 79% and PR in 33% of the tumors. This group of aggressive tumors was highly proliferative as indicated by Ki-67 index (mean 38.9%), and in some cases proliferation appeared to be mainly located to areas with a high ER density. The majority of cases (76%), both receptor-positive and -negative, overexpressed p53. High ER expression was related to a lower apoptotic activity as compared with tumors with a low expression of the ER (p = 0.008). Serum progesterone in itself did not show any clear relationship to steroid receptor status, expression of Ki-67, p53, Bcl-2 or signs of apoptosis. Survival in this small but homogeneous group of advanced epithelial ovarian cancers, showed an improved survival rate in patients with high serum progesterone, especially in combination with expression of progesterone receptors (p = 0.04). In conclusion, estrogen and progesterone receptors in parallel with deranged p53 and Ki-67 were expressed to a great extent. The finding of a lower apoptotic activity in tumors with a high expression of ER and an indication of increased proliferation in areas with high ER density gives a rationale for antiestrogen therapy even in poorly differentiated epithelial ovarian cancers. Improved survival is related to serum progesterone, especially in combination with PR expression.

Type specificity and significance of different isotypes of serum antibodies to human papillomavirus capsids.

Isotype-specific serum antibody responses against human papillomavirus (HPV) type 16 were evaluated by use of cross-sectional, prospective, and population-based seroepidemiologic studies. IgG1 and IgA were the most abundant isotypes. No sample contained IgG2, and <25 samples contained IgG3 or IgM. Total IgG, IgA, and IgG1 were HPV type specific and were associated with HPV-16 DNA (odds ratios [ORs], 5.4, 5.0, and 5.9, respectively; P<.001) but not with other HPV DNA (ORs, 1.2, 1.2, and 0.8, respectively; P value was not significant). Total IgG and IgG1 were strongly associated with number of lifetime sex partners (P<.001); IgA was only associated with number of recent sex partners and lifetime sex partners among younger women. Total IgG, IgG1, and IgA were associated with cervical intraepithelial neoplasia type III and also predicted risk of future cervical neoplasia. IgG and IgG1 appeared to mark lifetime cumulative exposure, whereas IgA may mark recent or ongoing infection.

A population-based study of human papillomavirus deoxyribonucleic acid testing for predicting cervical intraepithelial neoplasia.

OBJECTIVE: Our purpose was to determine the predictive values of primary or secondary screening for cervical human papillomavirus infection for cytologic detection of cervical intraepithelial neoplasia. STUDY DESIGN: Most of the 254 women referred for colposcopy in Västerbotten County in Sweden during October 1993 through December 1995 and 320 age-matched women from the general population were screened for human papillomavirus deoxyribonucleic acid by nested general-primer polymerase chain reaction. RESULTS: Ninety-six percent of women with high-grade cervical intraepithelial neoplasia had human papillomavirus, compared with 4% of women with normal findings (odds ratio 606; 95% confidence interval 137 to 5607). Thirty-seven percent of referred women and 48% of referred women >39 years old had mostly minor cytologic abnormalities with no human papillomavirus. The human papillomavirus-associated positive predictive value for cervical intraepithelial neoplasia was 76% in the colposcopy group and 11% in the general population, whereas the negative predictive value was >97% in both populations. CONCLUSION: Testing for human papillomavirus deoxyribonucleic acid seems diagnostically useful among women referred for colposcopy.

Peritoneal fluid and HCG influence on steroid production from ovarian tumor tissue, in vitro.

Steroids are produced by malignant and benign epithelial ovarian tumor tissue in vitro, but the regulation is unknown. The effect of peritoneal fluid and beta-HCG on steroid production was analysed. Tissue from 17 malignant or benign epithelial ovarian tumors and 6 normal postmenopausal ovaries were incubated. In 11 cases tissue was incubated with and without addition of the patient's own peritoneal fluid (Part I). Tissue from 22 ovaries was incubated with and without HCG (100 IU/ml medium), (Part II). Furthermore, the release from tumorous and control ovaries of beta-HCG, progesterone, androstenedione and estradiol measured using radioimmunoassay (Part III). Peritoneal fluid stimulated the release of progesterone from both malignant and benign tissue and androstenedione or estradiol stimulated release from benign tissue (Part I). There was no stimulatory effect of HCG on steroid release from malignant tissue. HCG stimulated release of estradiol in benign tissue (Part II). All malignant tumors and 4 out of 6 benign tumors released beta-HCG (Part III). There seems to exist factors in peritoneal fluid which are able to stimulate steroid production from ovarian tumors.

Pap smear screening and changes in cervical cancer mortality in Sweden.

OBJECTIVES: Age-adjusted incidence of cervical carcinoma has fallen dramatically in Sweden in recent decades. This investigation is an attempt to evaluate the effectiveness of the gynecologic Pap smear screening program in terms of reduction of mortality from cervical cancer. METHODS: Cervical cancer mortality trends in relation to age, calendar period, county and degree of screening activities in the population were analyzed. Multiplicative Poisson regression models were utilized. The reduction of mortality was attributed to the activities of cervical screening. RESULTS: The analysis gave a calculated 53% reduction in cervical cancer mortality (95% confidence limits 23-72%), attributable to screening. CONCLUSIONS: The study supports the hypothesis that gynecological Pap smear screening has had an important impact on the reduction in cervical cancer mortality.

Plasma prealbumin in women with epithelial ovarian carcinoma.

BACKGROUND: Epithelial ovarian carcinoma produces steroid hormones that may be of prognostic importance. The steroids are mainly bound to plasma albumin and sex hormone-binding globulin. Alterations in plasma protein levels influence hormonal effects. As plasma prealbumin may reflect changes in the patient's clinical status better than do albumin determinations, it is of interest to analyze prealbumin in patients with ovarian cancer. METHODS: Fifty-one postmenopausal or oophorectomized women with epithelial cancer of the ovary were studied. Plasma prealbumin was analyzed prior to and during chemotherapy. Tumor volumes were evaluated and blood samples were drawn for prealbumin analysis on four occasions at monthly intervals. Plasma levels were compared with one control group of postmenopausal women, one group of fertile women in the follicular phase of the menstrual cycle, and one control group of postmenopausal women with nongynecologic disseminated malignant disease. RESULTS: Prealbumin concentrations are lower in women with carcinoma of the ovary than in postmenopausal controls and the levels correlate inversely to tumor volume. Prealbumin concentrations are decreased in the large tumor group, advanced tumor stage group and in the control group with nongynecologic disseminated malignant disease. During chemotherapy, plasma prealbumin increases concomitantly with the reduction of tumor volume. Initial plasma prealbumin concentration seems to have prognostic importance. CONCLUSIONS: Prealbumin may be a sensitive indicator of disturbances in protein metabolism. It may reflect changes in the patient's clinical status better than do albumin determinations. Prealbumin concentration seems to have a prognostic importance in women with epithelial ovarian carcinoma. CONDENSATION: Prealbumin is studied in women with epithelial ovarian carcinoma prior to and during chemotherapy, and is found to vary inversely with changes in tumor volume.

Steroid production in different parts of malignant and benign ovarian tumors in vitro.

Pieces of ovaries and tumors from 45 patients (19 with malignant epithelial tumors, 14 with benign epithelial tumors, and 12 with normal postmenopausal ovaries) were incubated, and the release of steroid hormones from different parts of the tumors and from the contralateral ovaries was measured. Tumor tissue (mainly tumor cells with a small number of stromal cells), tumor base tissue (more stromal cells than tumor cells), and control ovaries were preincubated in oxygenated 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-minimum essential medium buffer at 37 degrees C for 30 min followed by a 3-h incubation in fresh, oxygenated medium. Progesterone, androstenedione, testosterone, and estradiol were measured in the medium by radioimmunoassay at the end of the incubation period. Malignant tumors released more progesterone and androstenedione than benign tumors or postmenopausal control ovaries. In contrast, benign tumors released more testosterone than malignant tumors or control ovaries. Release of estradiol was low and not significantly different among control ovaries and malignant and benign tumor tissue. Different parts of the tumors differed in steroid hormone release. Tissue samples containing more tumor cells than stromal cells released more progesterone than those with predominantly stromal cells. Thus, malignant tumors had an active steroid secretion. Progesterone was the main steroid released.

Preliminary experience with intraperitoneal catheters in the treatment of ovarian cancer.

Twenty-nine patients with ovarian carcinoma were treated with intraperitoneal cisplatin. Insertion of an intraabdominal catheter was performed during second-look laparotomy. Only one serious complication occurred with abdominal pain, ileus and local peritonitis. Otherwise, the major problems were of a technical nature with separation of the plastic tube from the metallic part of the catheter in 3 cases. In 8 of 29 patients intraperitoneal treatment was discontinued mainly due to local problems at the site of the pot. The procedure is otherwise safe and well tolerated by patients.

Relationship between CA 125 and progesterone production in women with ovarian carcinoma.

CA 125 and steroid production is compared in a group of 48 women with ovarian epithelial carcinoma. The histologic types were I C (n = 20), II C (n = 5), III C (n = 11), or V (n = 12). The number of patients in Stage I was six; Stage II, 11; Stage III, 16; and Stage IV, 15. All patients were naturally or surgically postmenopausal. Blood samples were taken at the first admission to the hospital and 14 cases with large tumors were followed with monthly sampling during chemotherapy, and in 13 cases until a recurrence of the tumor. CA 125 and steroid production were analyzed using radioimmunoassay. The results show a high correlation between initial CA 125 and especially progesterone plasma concentration. Both decreases during chemotherapy parallel the shrinkage of the tumor and increase 1 to 4 months before recurrence. Progesterone and CA 125 together predicted all recurrences but none of the factors alone. The prognostic value for 5-year survival was somewhat higher for progesterone than CA 125. CA 125 correlated highly with sex hormone binding globulin (SHBG) and negatively with albumin. The correlation may be due to the intercorrelation with tumor burden.

Human chorionic gonadotropin, follicle-stimulating hormone, and luteinizing hormone in patients with epithelial ovarian carcinoma.

Plasma levels of human chorionic gonadotropin (hCG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were studied in patients with epithelial ovarian carcinoma prior to and during chemotherapy. Blood samples were drawn for radioimmunoassay at monthly intervals. Plasma concentrations were compared to those of three different control groups: healthy post-menopausal women (PM), fertile women in the follicular phase of the menstrual cycle (FPh), and postmenopausal women with nongynecologic disseminated malignant disease (DMD). The hCG level was elevated in women with great tumor burden, such as large tumor volume, FIGO stage IV, and histologic type V. LH and FSH levels showed the reverse pattern. hCG concentration decreased during chemotherapy, whereas LH increased. Initial plasma concentrations were not found to have prognostic importance. We discuss the possibility that hCG is produced by the tumor, which stimulates steroid hormone production by the stroma, which, in turn, exerts negative feedback on FSH production by the pituitary.

Significance of initial plasma steroid concentrations in the prognosis of 'nonendocrine' malignant ovarian tumors.

The prognostic value of progesterone (P), androstenedione (A), Estradiol, Testosterone, 20 alpha-hydroxy-progesterone, sex hormone binding globulin, and albumin (Alb) was investigated in 51 women with ovarian carcinoma. All patients had observation periods greater than 5 years. The plasma concentrations of P, A, and Alb and the P/Alb and A/Alb ratios showed a significant correlation with the observation time of the patients. P, P/Alb, Alb, and A/Alb separately or in combination showed the highest prognostic specificity and sensitivity. The patients with a plasma concentration above an optimal limit or above mean + 2 SD of a control group of 20 postmenopausal women were grouped together. The groups with P/Alb, A, A/Alb, and Alb above the limit showed an equal survival rate as patients in FIGO stage IV. Patients with a high A/Alb ratio and a high testosterone concentration showed an even poorer prognosis than FIGO stage IV patients. Among the patients in stage IV the A/Alb ratio and sex hormone binding globulin gave additional prognostic information on the stage. The steroid concentration is not only related to tumor volume, as shown earlier, but also reflects the prognosis of the disease.

Plasma level of estradiol in patients with ovarian malignant tumors.

Plasma concentration of estradiol has been investigated in women with epithelial ovarian carcinoma. Forty-nine postmenopausal and/or oophorectomized women with no other malignant or endocrine disease were included in the study. All FIGO stages and the histological types IC, IIC, IIIC, and V were represented. Tumor volumes were evaluated once a month using bimanual recto-vaginal palpation under full anesthesia. Blood samples were drawn for estradiol radioimmunoassay at monthly intervals during 3 months. Plasma levels were compared with a control group of postmenopausal women with no internal disease or medication. The results show a significantly higher concentration in patients with large tumor volume compared to postmenopausal controls and a positive relationship between tumor volume, stage, and plasma estradiol level. Histological type seems to be of less importance and secondary to tumor volume. During chemotherapy the plasma concentration of estradiol decreased rapidly with the reduction of tumor volume.

Androstenedione production by malignant epithelial ovarian tumors.

The concentration of plasma androstenedione in women with malignant epithelial ovarian tumors is investigated. Fifty-one postmenopausal and/or oophorectomized women with no other malignant or endocrine disease are included in the study. All FIGO stages and the histologic types I C, II C, III C, and IV are represented. The tumor volumes were evaluated once a month using bimanual rectovaginal palpation under anesthesia. Four blood samples were drawn for androstenedione radioimmunoassay at monthly intervals. The plasma levels were compared with those of a control group of postmenopausal women and a control group of fertile women in the follicular phase of the menstrual cycle. The results show a relationship between tumor volume and plasma androstenedione level. Histologic type and FIGO stage seem to be of subordinate importance and secondary to tumor volume. During chemotherapy the plasma concentration of androstenedione decreased parallel to the reduction in tumor volume. The initial plasma androstenedione concentration seems to have prognostic importance.

Plasma steroid hormones in women with epithelial ovarian carcinoma.

Plasma concentrations of steroid hormones were investigated in 51 postmenopausal or bilaterally oophorectomized women with epithelial ovarian carcinoma, but free from other malignant or endocrine disease. All FIGO stages and the histological types IC, IIC, IIIC and V are represented. Plasma levels of progesterone (P), 20 alpha-hydroxyprogesterone (20 alpha-OH-P), androstenedione (A), testosterone (T), estradiol (E2), Sex-Hormone-Binding Globulin (SHBG) and albumin were analysed, and unbound fractions of testosterone (UT) and estradiol (UE) were calculated. Blood samples were drawn for radio-immunoassay prior to and during chemotherapy at monthly intervals on four occasions. Thus, it was possible to study how plasma levels of steroid hormones are influenced by tumor volume, stage, histological type, effect of chemotherapy, recurrence of disease, and finally, whether determination of the initial plasma level of any steroid hormone, separately or in combination, may give an indication as to the prognosis of the disease. Plasma hormone levels were also compared with those of a control group of postmenopausal women (PM), a control group of fertile women in early follicular phase of the menstrual cycle (FPh), and, finally, with a control group of postmenopausal women with a non-gynecologic disseminated malignant disease (DMD). A relationship has been found between tumor volume and plasma concentration of the investigated hormones. Corresponding relationships have also been found vis-à-vis FIGO stage and histological type, though probably secondary to tumor volume. With reduction of tumor volume during treatment, a concomitant decrease in plasma concentration has been found concerning P, A and E2. The unbound fraction of T was not influenced by therapy and did not differ from PM controls. With the combined determination of P and A it has been possible to detect recurrence of disease earlier than by clinical means in the majority of cases. Certain combinations of the initial values of P, A, T and A/alb seem to predict prognosis as well as or better than does FIGO stage. In conclusion, a correlation between steroidogenesis and progress of epithelial ovarian carcinoma seems to exist. Steroidogenesis might also reflect the prognosis of the disease.

Testosterone, SHBG and albumin in patients with ovarian carcinoma.

Plasma testosterone, unbound testosterone, Sex Hormone Binding Globulin (SHBG) and albumin were studied in women with 'non-endocrine' ovarian carcinoma prior to and during chemotherapy. Fifty-one postmenopausal or oophorectomized women with cancer of the ovary were studied. The histologic types were IC, IIC, IIIC, V and FIGO stages I-IV. Tumor volumes were evaluated once a month using bimanual recto-vaginal palpation under anesthesia. Blood samples were drawn for testosterone radio-immunoassay, SHBG and albumin analysis on four occasions at monthly intervals. Plasma levels were compared with a control group of postmenopausal women, a control group of fertile women in the follicular phase of the menstrual cycle, and finally a control group of postmenopausal women with non-gynecologic disseminated malignant disease. Testosterone concentrations were found to be higher in women with carcinoma of the ovary than in postmenopausal controls and showed a relationship to tumor volume. Histologic type and FIGO stage were found to be less closely related to plasma testosterone concentration. No significant change was found in the unbound testosterone fraction. SHBG concentrations were elevated in the Large-tumor group. Albumin concentrations were decreased in the Large-tumor group, advanced tumor stage group and in the control group with non-gynecologic disseminated malignant disease.

Plasma progesterone and androstenedione in relation to changes in tumor volume and recurrence in women with ovarian carcinoma.

The concentrations of plasma progesterone and androstenedione were investigated in 13 postmenopausal women with malignant ovarian tumors who showed no signs of other malignant or endocrine disease. FIGO stages III and IV were represented and histological types were mainly Ic and V. Tumor volumes were generally evaluated once a month using bimanual rectovaginal palpation under anesthesia. Blood samples were drawn for progesterone and androstenedione radioimmunoassay at every admittance to hospital. In 12 of the 13 patients the plasma levels of progesterone and in 10 the plasma levels of androstenedione decreased in parallel with the reduction in tumor volume and increased again when recurrence occurred. The plasma levels at diagnosis of recurrence of tumor and the levels when the largest tumor volume was demonstrated were compared to the preceding values and found to be significantly higher. In order to evaluate if progesterone or androstenedione could predict recurrence of tumor, plasma levels at certain intervals before recurrence were compared to the preceding value. Significant rise was considered to have occurred when plasma concentration had risen to twice the coefficient of variation of the assay above the previous value and continued to rise. Plasma progesterone indicated recurrence of tumor in 8 cases at least 1 month before recurrence was palpable. Plasma concentration of androstenedione was found to be useful in predicting recurrence in 5 cases 1 month or more before recurrence was palpable. A group of postmenopausal women with disseminated malignant disease of nongenital type was compared to the control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma 20 alpha-OH-progesterone in women with malignant epithelial 'non-endocrine' ovarian tumors.

The production of 20 alpha-OH-progesterone (20 alpha-OH-P) in women with malignant epithelial ovarian tumors was investigated. The study material comprised 51 postmenopausal and/or oophorectomized women with ovarian carcinoma, including the histological types Ic, IIc, IIIc and V and FIGO stages I-IV. Their tumor volumes were evaluated once a month using bimanual recto-vaginal palpation under anesthesia. Blood samples were drawn for 20 alpha-OH-P radio-immunoassay at monthly intervals for 3 months. The plasma levels were compared with those of a control group of postmenopausal women. The results show a relationship between tumor volume and plasma 20 alpha-OH-P level. Another finding is that endometrioid ovarian cancer (histologically IIIc) showed a significantly lower 20 alpha-OH-P production than the other types. The reason for this is discussed.

Progesterone as a possible tumor marker for "nonendocrine" ovarian malignant tumors.

Fifty-one postmenopausal or oophorectomized women with cancer of the ovary were studied. The histologic types were IC, IIC, IIIC, V, and FIGO Stages I-IV. Their tumor volumes were evaluated once a month using bimanual recto-vaginal palpation under anesthesia. Blood samples were drawn for progesterone radioimmunoassay at monthly intervals for 4 months. The plasma levels were compared with those of a control group of postmenopausal women and a control group of fertile women in the follicular phase of the menstrual cycle. The results show a relationship between tumor volume and plasma progesterone level. Histologic type and FIGO stage seem to be less important. During chemotherapy the plasma progesterone value decreased with the reduction in tumor volume. Women bilaterally oophorectomized and radically operated showed a lower plasma progesterone level than both the control groups, which indicates significant progesterone production in the postmenopausal ovary. The results suggest that progesterone may be used as a tumor marker in "nonendocrine" ovarian tumors.