Is potential to produce inhibins related to prognosis in ovarian granulosa cell tumors?

OBJECTIVE: The prognosis of ovarian granulosa cell tumors is difficult to predict by conventional histological methods. STUDY DESIGN: The tumors of 30 patients operated on for a granulosa cell tumor were retrospectively studied for the expression of the inhibin alpha-subunit. The immunohistochemical staining results were correlated to the FIGO stage of the tumor and the prognosis of the patients. RESULTS: Twenty-six (87%) of the ovarian granulosa cell tumors stained positively for the inhibin alpha-subunit. All FIGO stage I and II tumors expressed inhibin alpha-subunit. All FIGO stage I and II tumors expressed inhibin, whereas the majority of stages III and IV did not (p=0.001, chi2-test). The survival of the patients with inhibin immunopositive tumors was significantly longer (median 183 months, SE 41, p=0.000, log rank test) than that of patients without inhibin expression (median 2.5 months, SE 5.25). CONCLUSIONS: Patients with ovarian granulosa cell tumors with a potential to produce the inhibin alpha-subunit may have a more favorable prognosis than those with inhibin immunonegative tumors.

Inhibin A, B and pro-alphaC in serum and peritoneal fluid in postmenopausal patients with ovarian tumors.

OBJECTIVE: To compare serum and peritoneal fluid concentrations of inhibin A, B, and pro-alphaC in women with ovarian tumors. METHODS: Serum and peritoneal fluid samples were taken from 41 postmenopausal women operated on for an ovarian tumor. Twenty-one patients with endometrial cancer formed a control group. Serum and peritoneal fluid inhibin A, B, and pro-alphaC concentrations, and serum FSH and tumor marker CA 125 (study group only) concentrations were analyzed. RESULTS: Inhibin A was found in low concentrations (median 4.1pg/ml, range <2-29pg/ml) in serum in most postmenopausal patients with epithelial ovarian carcinoma, whereas inhibin B was not measurable. Inhibin pro-alphaC circulated in high concentrations (median 125pg/ml, range 37->1000pg/ml). All inhibins were found in clearly greater concentrations in the peritoneal fluid than in serum. International Federation of Gynecology and Obstetrics (FIGO) stage III-IV and poor differentiation grade were associated with significantly lower concentrations of inhibin A and pro-alphaC in the peritoneal fluid compared with stages I-II or low grade. This correlation was not found in the serum concentrations of inhibin A or pro-alphaC. In the control group, no dimeric inhibins were found in serum, and pro-alphaC circulated in median concentrations of 47pg/ml (range 12-174pg/ml). CONCLUSIONS: Postmenopausal patients with epithelial ovarian tumors had low concentrations of inhibin A and relatively high concentrations of inhibin pro-alphaC in serum. The peritoneal fluid concentrations of all inhibins far exceeded those in the serum. Relatively low concentrations of inhibin A and pro-alphaC in the peritoneal fluid of patients with ovarian cancer seem to be associated with high stage and grade and, to a lesser degree, with positive peritoneal cytology.

In the dose range of 0.5-2.0 mg/kg, acetylsalicylic acid does not affect prostacyclin production in hypertensive pregnancies.

OBJECTIVE: To determine the dose of acetylsalicylic acid (ASA), that inhibits the production of the vasoconstrictive, aggregatory thromboxane A2 while sparing the production of the vasodilatory antiaggregatory prostacyclin. DESIGN: A controlled study comparing the effects of three doses of ASA on the production of thromboxane A2 and prostacyclin. METHODS: Seven pregnant hypertensive patients and five non-pregnant healthy women received 0.5, 1.0 and 2.0 mg/kg/day of ASA, each dose for 10-12 days, the treatment periods following each other immediately. Seven normotensive pregnant women served as controls and were given no ASA. Blood and urine samples were taken at baseline and after the treatment periods to determine serum thromboxane B2 and the urinary 2.3-dinor-6-ketoprostaglandin F1alpha and 11-dehydrothromboxaneB2, the major stable metabolites of prostacyclin and thromboxane A2, respectively. RESULTS: The urinary excretion of 11-dehydrothromboxaneB2 was significantly higher in both hypertensive (34.9+/-18.3 pg/micromol creatinine) and normotensive (39.3+/-14.4 pg/micromol creatinine) pregnant women than in non-pregnant women (14.8+/-6.4 pg/micromol creatinine). The urinary excretion of 2.3-dinor-6-ketoprostaglandinF1alpha was also higher in normotensive pregnant women (93.9+/-50.9 pg/micromol creatinine) than in non-pregnant women (18.2+/-11.3 pg/micromol creatinine). The excretion rate of 2.3-dinor-6-ketoprostaglandinF1alpha in hypertensive patients was lower than in normotensive pregnant women (44.7+/-24.2 pg/micromol creatinine). At baseline the urinary 2.3-dinor-6-ketoprostaglandin F1alpha/11-dehydrothromboxaneB2 ratio was almost the same in the hypertensive patients (1.6) and in the non-pregnant women (1.2). The ratio was 2.6 in normotensive pregnant women. In the hypertensive group, already the lowest dose of ASA inhibited urinary 11-dehydrothromboxaneB2 excretion significantly. Because none of the doses of ASA inhibited 2.3-dinor-6-ketoprostaglandinF1alpha production, the 2.3-dinor-6-ketoprostaglandinF1alpha/11-dehydrothromboxaneB2 ratio was shifted in the favor of prostacyclin at all dose levels. In the non-pregnant women, even the highest dose level of ASA failed to affect the ratio. CONCLUSION: In the dose range of 0.5-2.0 mg/kg/day, ASA has a favorable effect on the ratio of prostacyclin to thromboxane A2 in hypertensive pregnancies.

Ovarian cancer and gonadotropins in vitro: new evidence in favor of independence.

BACKGROUND: The aim of this study was to investigate whether newly established epithelial ovarian carcinoma cell lines secrete inhibins, and whether their proliferative and secretory activity can be regulated by gonadotropins. MATERIALS AND METHODS: Three recently characterized human epithelial ovarian carcinoma cell lines were exposed to human choriongonadotropin hCG and follicle stimulating hormone FSH. Cell proliferation was determined by counting. Secretory activity of the cell lines was studied by analyzing inhibin A, inhibin B, inhibin pro-aC, estradiol, progesterone, testosterone, and CA 125 concentrations from the medium. The expression of gonadotropin receptors was studied by RT-PCR. RESULTS: None of the cell lines were found to secrete any of the inhibins, progesterone or testosterone. Only UT-OC-4 cells secreted low levels of estradiol. Gonadotropin receptors were not expressed by any of the cell lines, and accordingly neither FSH nor hCG stimulated the growth of these cells. However, hCG had some dose dependent growth inhibitory effect on UT-OC-3. Passage 42 cells of UT-OC-3 secreted significantly more CA 125 than passages 8 cells (P = 0.000). CONCLUSIONS: The present results suggest that the carcinomatous epithelial cells of the ovary do not secrete inhibins. The serum inhibin levels previously detected in patients with epithelial ovarian carcinoma may therefore reflect an ovarian stromal response to carcinoma. The findings are also in favor of an independence of ovarian cancer of gonadotropins.

Ovarian testosterone secretion during perimenopause.

OBJECTIVE: The aim of the study was to investigate ovarian testosterone secretion during the last few years of reproductive life and after menopause. MATERIALS AND METHODS: Ovarian and peripheral venous levels of total testosterone were analyzed in 52 women aged 42-69 years (mean 51) undergoing hysterectomy with adnexal removal for benign indications at the Department of Obstetrics and Gynecology at Tampere University Hospital, Finland. The study population was divided into pre- (n = 19), peri- (n = 18) and postmenopausal (n = 15) women in addition to the classical division according to menstrual cycle. Corresponding serum estradiol, progesterone and gonadotropin levels were measured, and the degree of ovarian stromal hyperplasia was analyzed. RESULTS: The levels of all steroid hormones were higher in the ovarian vein than in the periphery. A significant positive correlation was found between age and ovarian vein testosterone levels (r = 0.3, P = 0.01). In premenopausal women, it was 1.5 nmol/l (median; range 0.78-6.0), in perimenopausal women 2.2 nmol/l (range 0.9-13.6), and 2.5 nmol/l (range 0.6-26.6) in postmenopause, respectively. Peripheral testosterone level did not increase with age. Ovarian stromal hyperplasia was significantly associated with increased testosterone secretion (P = 0.009). CONCLUSION: The ovary seems to increase the secretion of testosterone into circulation during the menopausal transition period, as the highest levels were measured in postmenopausal women. High testosterone levels in the ovarian vein, however, were not reflected in the peripheral venous blood.

Inhibin A and B in peri- and postmenopause.

OBJECTIVE: The aim of the study was to investigate the origin of inhibin A and B during the last years of the reproductive age and after menopause by measuring their levels in the ovarian and peripheral venous blood. METHODS: The study population consisted of 43 women, aged 42-69 years (mean 50), who underwent hysterectomy with ovarian removal for a benign disease. A total of 24 of them were in follicular phase, 11 in luteal phase, and eight were postmenopausal. Peripheral and ovarian venous blood was collected for measurement of inhibin A and B. In addition, sex steroid hormone and gonadotropin levels were measured. RESULTS: Ovarian venous inhibin B correlated significantly with ovarian estradiol secretion (r = 0.5, P = 0.001). The levels of inhibin B were significantly higher in the ovarian vein than in the peripheral vein (P = 0.006). The highest inhibin B concentrations were detected in the mid-proliferative (mid-follicular) phase (median 31.6 pg/ml range 25.9-47.9). In postmenopausal women, inhibin B was not detectable. No correlation between FSH and ovarian inhibin B was found. Inhibin A rose rapidly in late proliferative (late follicular) phase (median 28.5, range < 2-51.8) and dominated in the circulation throughout the luteal phase (median 20.9, range 8.8-60). For inhibin A, no concentration gradient existed between the ovarian and peripheral vein. Unlike inhibin B, inhibin A was detectable in ovarian and peripheral blood in postmenopausal women. A significant negative correlation between ovarian and peripheral inhibin A and FSH was found (r = -0.386, P = 0.015; r = -0.345, P = 0.034, respectively). CONCLUSION: Inhibin B correlates with ovarian estradiol secretion and seems to reflect follicular function. Inhibin A dominates in circulation during the luteal phase but is detectable at low concentrations both in follicular phase and even in postmenopause. Our findings suggest that inhibin A may play a role in FSH suppression in the female reproduction. In addition to the ovary, there may be extragondal source(s) of inhibin A.

Toremifene in postmenopausal breast cancer. Efficacy, safety and cost.

Toremifene is a chlorinated tamoxifen analogue that is indicated for the treatment of postmenopausal hormone-dependent breast cancer. It competes with estradiol for estrogen receptors and has growth-inhibitory effects on MCF-7 breast cancer cells. At concentrations < 10(-6) mol/L, this growth inhibition can be reversed by estradiol, but at higher concentrations toremifene is cytotoxic. In dimethylbenzanthracene (DMBA)-induced mammary cancer in rats, toremifene has been shown to decrease the number of new tumours and to inhibit the growth of existing tumours. Toremifene causes growth inhibition by suppressing mitosis and inducing apoptosis. The mechanism by which these events occur may involve the induction of transforming growth factor-beta 1 and inhibition of insulin-like growth factor-1 (mecasermin). Toremifene is primarily an antiestrogen, but it has some estrogen agonist properties in postmenopausal women. The latter are reflected by the fall in luteinising hormone and follicle-stimulating hormone levels and the rise in sex hormone-binding globulin levels that are associated with its use in most women. After estrogen priming, toremifene 68mg administered orally has been found to exert a similar antiestrogenic effect on the vaginal epithelium in postmenopausal women as tamoxifen 60mg. The half-life of toremifene in plasma is 5 days, and the drug is > 99% bound to plasma proteins. The main metabolites of toremifene are N-demethyl-toremifene and deaminohydroxy-toremifene. Altered liver, but not kidney, function affects the pharmacokinetics of toremifene. Toremifene 60mg daily is as effective as tamoxifen 20mg daily in the treatment of postmenopausal hormone-dependent breast cancer, producing a response in about 50% of patients. Soft tissue and visceral metastases respond better to toremifene than bone metastases. Most of the adverse effects of toremifene are related to its activity at estrogen receptors and include hot flashes, vaginal discharge and nausea. Although toremifene decreases antithrombin III levels slightly, the incidence of thromboembolic complications is low. Thus far, no carcinogenic effects have been noted in humans, and preclinical data are mostly reassuring. Toremifene has favourable effects on serum lipids, and thus has potential in preventing coronary heart disease. Although toremifene is somewhat more expensive to use than tamoxifen, toremifene is an effective and well tolerated alternative to tamoxifen in the treatment of postmenopausal women with hormone-dependent breast cancer. No formal pharmacoeconomic comparisons of toremifene and tamoxifen have yet been published. Toremifene is potentially safer than tamoxifen in relation to carcinogenic effects and effects on serum lipids.

Prognostic significance of p53 expression in ovarian granulosa cell tumors.

OBJECTIVE: The purpose of the study was to investigate the significance of p53 expression for the prognosis in patients with ovarian granulosa cell tumors (GCT). METHODS: The records of 30 patients operated on for GCT at Tampere University Hospital, Finland, were reviewed. The mean age at the time of the diagnosis was 55 years. Twenty-one of the tumors were of FIGO stage I, three were of stage II, three were of stage III, and three were of stage IV. Paraffin-embedded tumor specimens were analyzed by immunohistochemistry for expression of mutated p53 protein and by flow cytometry. RESULTS: Eleven tumors were positive for p53 and 19 were negative. The median crude survival of p53-negative patients was 10 times that of p53-positive ones (210 months vs 21 months, P = 0.037, log-rank test). The association between p53 immunoreactivity and stage was statistically significant (P = 0.026 Pearson chi2 test), while there was no association between p53 expression and DNA ploidy or S-phase fraction. CONCLUSION: Although the results should be considered as preliminary, expression of mutated p53 in ovarian granulosa cell tumors seems to be associated with unfavorable prognosis.