Robot-assisted abdominal laparoscopic radical trachelectomy.

BACKGROUND: Radical trachelectomy in conjunction with pelvic lymphadenectomy is an established method to preserve fertility in early cases of cervical cancer. The radical trachelectomy is usually performed vaginally despite the initial use of laparoscopy for the lymphadenectomy. The complexity of a laparoscopic abdominal trachelectomy may explain this dual approach. Here we describe the surgical technique of a robot-assisted laparoscopic radical trachelectomy with lymphatic mapping using a radiotracer and without a vaginal approach. CASES AND SURGICAL TECHNIQUE: Two nulliparous women with early cervical cancer underwent a laparoscopic radical trachelectomy and pelvic lymphadenectomy with the assistance of the da Vinci robot (Intuitive Surgical Inc, Sunnyvale, CA). After the sentinel lymph nodes were found negative on frozen section, the parametria, paracolpia and sacrouterine ligaments were dissected sparing the main branches of the uterine arteries. Following ligation of the descending branches of the uterine arteries the cervix and the vagina were transsected using monopolar diathermia and the vagina was sutured to the remaining cervix. Finally, a permanent cerclage was placed. Time for surgery was 387 and 358 min respectively. No perioperative complications were noted and the postoperative period was uneventful in both cases. CONCLUSIONS: Robot-assisted laparoscopic abdominal trachelectomy is a feasible alternative to a combined laparoscopic and vaginal approach.

Expression of the oxytocin gene, but not the vasopressin gene, in the rat uterus during pregnancy: influence of oestradiol and progesterone.

Oxytocin (OT) and vasopressin (VP) are neurohypophyseal hormones with potent stimulatory actions on the uterus. In order to determine whether these hormones may have a paracrine action on the uterus, OT and VP gene expression was studied in myometrium from pregnant rats at gestational ages of 14 and 20 days, and from ovariectomized animals treated with oestradiol and progesterone. OT and VP mRNA concentrations were measured using real-time quantitative reverse transcription-PCR, and OT- and VP-like immunoreactivities were determined using RIA. OT mRNA was detected in the uterus from pregnant rats, but did not differ between the groups of different gestational ages. Oestradiol significantly (P<0.05) stimulated OT gene expression in ovariectomized rats. Progesterone alone was without effect on OT mRNA concentrations, but significantly (P<0.05) reduced the oestradiol-induced OT mRNA accumulation. The OT-like immunoreactivity in an extract of myometrium from pregnant rats was eluted from a reverse-phase HPLC column with a retention time identical to that of synthetic OT. Neither VP mRNA nor VP-like immunoreactivity was detected in the myometrium from pregnant or ovariectomized rats. The study demonstrates steroid-dependent expression of the OT gene in the rat uterus and processing of uterine preprooxytocin to the mature nonapeptide. The data support the theory that this peptide may act in a paracrine pathway. No evidence was found for the presence of VP in the uterus so that, if the hormone is involved in a stimulatory action on this tissue, it probably acts via an endocrine mechanism.

ONO-8815Ly, an EP2 agonist that markedly inhibits uterine contractions in women.

OBJECTIVE: To determine the effect of ONO-8815Ly on uterine contractions. DESIGN: A randomised, double-blind, placebo-controlled, dose-ascending, cross-over study. SETTING: Department of Obstetrics and Gynaecology, University Hospital of Lund, Sweden. POPULATION: Seventeen, healthy, parous and permanently sterilised women. METHODS: Intrauterine pressure was recorded on days 1-3 of bleeding of two menstruations. Subjects were intravenously treated with 4 or 8 microg/minute of ONO-8815Ly or placebo for 130 minutes. Intravenous bolus injections of oxytocin, 50 pmol/kg body weight, were given 10 minutes before, during infusion after 60 and 120 minutes and 60 minutes after completion of infusion. The plasma concentrations of ONO-8815Ly were measured in samples obtained immediately before each oxytocin injection. MAIN OUTCOME MEASURE: Area under pressure recording curve (AUC) 10 minutes before and after each oxytocin injection. RESULTS: Twelve women, six in each dose group, completed both recordings. Of these, two women of each group were not included in efficacy analysis due to non-responsiveness to oxytocin or missing baseline value. The AUC over 10 minutes before oxytocin injection after 60 minutes of infusion of ONO-8815Ly at 4 and 8 microg/minute was reduced to 21% and 37% of that before infusion, respectively. The AUC after oxytocin at that time amounted to 21% and 19%, respectively, of that before infusion. The activity and responsiveness remained low after 120 minutes but started to return to baseline 60 minutes after stopping infusion. Placebo had no effect. CONCLUSIONS: ONO-8815Ly is a potent inhibitor of spontaneous uterine contractility in non-pregnant women and it reduces the uterine response to oxytocin injections.

Laparoscopic colposuspension: a short term urodynamic follow-up and a three-year questionnaire-study.

BACKGROUND: The purpose of the study was to evaluate outcome, urodynamic correlates and adverse effects of laparoscopic colposuspension using polytetrafluoroethylene sutures. METHODS: Eighty-five consecutive women with primary stress urinary incontinence at one university hospital were included in this prospective non-controlled study. During videolaparoscopic surgery, two polytetrafluoroethylene sutures were placed on each side of the urethra and fixed to the Cooper ligaments. Pre- and postoperative clinical and urodynamic evaluations, including pad-test, were performed. A mailed questionnaire was used to evaluate cure-rate and complication-rate three years after surgery. RESULTS: At follow-up examination, we considered 62 of 76 women (82%) as being cured, ten (13%) improved, and four (5%) as being failures. The questionnaires were returned by 80 women; 41 (51%) considering themselves as cured and 31 (39%) improved, and eight women (10%) as unimproved or minimally improved. Clinical outcome was not associated with alterations in urethral functional length or in urethral closing pressure. Short preoperative urethral functional length was associated with failure (p=0.04).The incidence of new onset urge symptoms and of new onset recto/enterocele was 13% and 9% respectively. CONCLUSIONS: Laparoscopic colposuspension resulted in acceptable cure rate in short-, and medium long term evaluation. However, a decline in cure rate was observed. Cured women had significantly longer preoperative urethral functional length than women still leaking after surgery.

Effect of SR49059, an orally active V1a vasopressin receptor antagonist, in the prevention of dysmenorrhoea.

OBJECTIVE: To investigate the clinical effect of SR49059 when given shortly before the onset of menstruation as a preventative treatment of dysmenorrhoea. DESIGN: A double-blind, randomised, placebo-controlled, cross-over trial in complete block design (three periods, three treatments). SETTING: A clinical research organisation in Paris, France. PARTICIPANTS: Women aged 18-35 years suffering from primary dysmenorrhoea. INTERVENTIONS: In each of three menstrual cycles, women reported to the study centre and were given a daily dose of either placebo, 100 mg or 300 mg SR49059 from a minimum of 4 hours up to a maximum of three days before the onset of bleeding and/or menstrual pain. If this did not control the pain, women were allowed once a day to take a second dose of study treatment providing that at least 4 hours had passed since the first drug intake. MAIN OUTCOME MEASURES: Intensity of menstrual pain recorded by means of a visual analogue scale. Rating of symptoms of dysmenorrhoea (mainly back and pelvic pain) in relation to functional capacity (Sultan score). Self-assessment of menstrual blood loss in a menstrual diary record. RESULTS: Analysis of intensity of menstrual pain, as recorded by visual analogue scale and Sultan pain score (back and pelvic pain) during the first 24 hours of dysmenorrhoea, showed a dose-related effect of SR49059. The 300 mg dose of SR49059 was significantly more effective than placebo. Similarly, a dose-related effect of SR49059 was shown on total Sultan score. SR49059 was well tolerated and no significant effect on the bleeding pattern was noted. CONCLUSIONS: This study showed for the first time a therapeutic effect of an orally active vasopressin V1a receptor antagonist in the prevention of dysmenorrhoea. Further studies are required to examine effect mechanisms and determine effective doses.

Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women.

OBJECTIVE: To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential. DESIGN: Receptor binding studies on transfected cell lines. In vitro contractility studies of human myometrium. SETTING: The Research Laboratory of Sanofi Recherche, Centre de Toulouse, France and the Departments of Obstetrics and Gynecology, Lund University Hospital, Sweden and Bialystok University Hospital, Poland. PARTICIPANTS: Nine women delivered by caesarean section preterm and 37 delivered at term for routine obstetric indications. INTERVENTIONS: The binding affinities of oxytocin, arginine vasopressin, atosiban (1-deamino-2-D-Tyr(OEt)-4-Thr-8-Om-oxytocin), SR 49059 and SR 121463 for the human oxytocin and different subtypes of vasopressin receptors were determined. Concentration-response curves with oxytocin and arginine vasopressin were recorded on myometrium from preterm- and term-delivered women in control experiments and in the presence of 2.5 and 10 nmol/L of SR 49059. Furthermore, using term myometrium, the influence of SR 49059 and SR 121463 in concentrations of 3, 10, 30 and 100 nmol/L on responses to the EC50 concentrations of oxytocin and vasopressin were compared. MAIN OUTCOME MEASURES: Receptor binding affinities. In vitro contractile effects and their inhibitions. RESULTS: Oxytocin had a high affinity for the oxytocin receptor (K(i) in mean = 6.8 nmol/L) and bound, to some extent, to the vasopressin V1a receptor (K(i) = 34.9 nmol/L). Vasopressin displayed higher affinities for vasopressin V1a, V1b and V2 receptors (K(i) = 1.4, 0.8 and 4.2 nmol/L, respectively) than for the oxytocin receptor (K(i) = 48 nmol/L). Atosiban and SR 49059 both had a high affinity for the vasopressin V1a receptor (K(i) = 4.7 and 7.2 nmol/L, respectively, and a moderate one for the oxytocin receptor (K(i) = 397 and 340 nmol/L, respectively). SR 121463 exerted a predominant binding to the V2 receptor (K(i) = 3.0 nmol/L). In the concentration-response experiments levels of up to 10 nmol/L of SR 49059 had no influence on the effect of oxytocin on myometrium from women preterm and at term pregnancy. However, a concentration-dependent inhibition of the responses of both these type of tissues to vasopressin was seen. The effects of EC50 concentrations of oxytocin and vasopressin on term pregnant myometrium were markedly inhibited by 10 nmol/L and higher concentrations of SR 49059, the inhibition of the response to vasopressin being more pronounced than that of the oxytocin response. SR 121463 at maximal concentration only caused slight inhibitions of the oxytocin and vasopressin responses. CONCLUSIONS: Atosiban and SR 49059 both have moderate binding affinities for the human oxytocin receptor and high binding affinities for the vasopressin V1a one. We demonstrated that SR 49059 inhibits the response of term myometrium to oxytocin and that of both preterm and term myometrium to vasopressin. These observations suggest a therapeutic potential of SR 49059 in preterm labour. The vasopressin V2 receptor is apparently not involved to any significant degree in the activation of the pregnant human uterus.

Osmotically-induced release of vasopressin and oxytocin in non-pregnant women--influence of estrogen and progesterone.

BACKGROUND: Circulating vasopressin and oxytocin are influenced by ovarian steroid blood levels, but the effect of estrogen and progestogen treatment on induced release of the posterior pituitary hormones is not clear. METHODS: Eight postmenopausal women who had not been on hormonal replacement therapy for at least two months were included in the study. The women were treated for four weeks with transdermal administration of estradiol-17beta in a daily dose of 100 microg with the addition of 5 mg tablets of medoxyprogesterone twice daily for the last two weeks. A 25 minute intravenous infusion of hypertonic saline (0.06 mg/kg/min) was given before hormonal treatment, and after two and four weeks with serial plasma sampling for assay of vasopressin and oxytocin. RESULTS: The mean basal concentration of vasopressin, which was 0.83+/-0.13 (SE) pmol/L before hormonal treatment, increased to a statistically significant degree after estradiol alone to 1.18+/-0.11 pmol/L and decreased after combined estrogen/progestogen treatment to 0.31+/-0.02 pmol/L. Sodium concentration and osmolality increased in a similar way during all three infusions, but the resultant increase in vasopressin concentration was significantly smaller and slower after treatment with estradiol alone than in the first experiment without pretreatment. The areas under the concentration curve for the second and third infusion were significantly smaller than when no hormone treatment was given. The induced hyperosmolality also caused a rise in oxytocin levels, but no influence of ovarian hormone treatment was observed. CONCLUSIONS: Ovarian hormone administration influences vasopressin secretion, affecting both the basal levels in plasma and the responses to an increase in plasma osmolality. The influence of ovarian hormones on oxytocin secretion is minimal.

Effects of the vasopressin V1a receptor antagonist, SR 49059, on the response of human uterine arteries to vasopressin and other vasoactive substances.

BACKGROUND: Arginine vasopressin (AVP) activates the uterus via V1a receptors and is apparently an important factor for the myometrial hyperactivity, uterine ischemia and pain of primary dysmenorrhea. The orally active and selective, non-peptide AVP1a receptor antagonist, SR 49059, has been shown to inhibit the myometrial action of AVP, but the specific influence of this substance on the effects of AVP and other vasoactive agents on human uterine arteries is unknown. METHODS: Concentration-responses of AVP on isolated medium-sized human uterine arteries were studied after incubation with only vehicle (DMSO, 0.1%) and with SR 49059 in concentrations of 0.5, 2.5 and 10 nmol/L. Furthermore, the concentration-responses of AVP were investigated without and with SR 49059 (2 and 10 nmol/L) on small and medium-sized arteries. Finally, the influence of 2.5 nmol/L of SR 49059 on concentration-responses of endothelin-1, noradrenaline and prostaglandin F2 alpha was studied. RESULTS: The EC50 for AVP on medium-sized arteries was 0.53 +/- 13 nmol/L. SR 49059 caused a competitive, dose-dependent inhibition of AVP-responses, the highest concentration giving an EC50 of 460 nmol/L. The pA2 value was 9.84. The responses of the small artery preparations to AVP, both without and with the antagonist, were more pronounced than those of the medium-sized ones. The vasoconstrictive effects of endothelin-1, noradrenaline and prostaglandin F2 alpha were less pronounced than those of AVP and unaffected by pre-exposure to SR 49059. CONCLUSIONS: The high potency of AVP on human uterine arteries, particularly those of small size, supports an involvement of the peptide in the regulation of uterine blood flow in both physiological and pathophysiological condition. SR 49059 is a potent and selective AVP V1a receptor antagonist in the smooth muscle of human uterine arteries.

Treatment of preterm labor with the oxytocin and vasopressin antagonist Atosiban.

Oxytocin is involved in the regulation of preterm and term labor but the exact effect mechanisms are not fully understood. A regulatory action by vasopressin may also exist. The concentrations of oxytocin and vasopressin V1a receptors in myometrium from pregnant women are high before and in the beginning of labor both preterm and at term. Atosiban has high affinity for both these receptors and is a competitive oxytocin and vasopressin antagonist. The inhibitory effect of Atosiban on oxytocin induced activity on isolated myometrium correlates significantly with the concentration of the oxytocin receptors. Inhibition of preterm contractions with Atosiban was first reported by Akerlund et al 1987. Goodwin et al compared the effect of Atosiban to placebo in threatening preterm labor and the antagonist was in this trial significantly more effective than placebo in reducing the frequency of contractions (55% vs. 23%, p < 0.001). The same authors also reported successful tocolysis with the drug in actual preterm labor. Atosiban is currently in phase III of clinical development and seems to have the same effectiveness but fewer side-effects compared to beta-mimetics. These properties suggests that Atosiban may offer advantages over existing therapies in acute treatment of preterm labor.

Effects of SR 49059, an orally active V1a vasopressin receptor antagonist, on vasopressin-induced uterine contractions.

OBJECTIVE: To test the effect of SR 49059, an orally active, nonpeptide, selective and specific antagonist of the vasopressin V1a receptors in humans. DESIGN: A placebo-controlled, double-blind, cross-over trial. SETTING: The Department of Obstetrics and Gynaecology, Lund University Hospital, Sweden. PARTICIPANTS: Twelve healthy women, who had previously been sterilised by tubal ligation. INTERVENTIONS: The women participated on days 1, 2 or 3 of two menstrual cycles, with intrauterine pressure recordings and intravenous bolus injections of 10 pmol/kg body weight of lysine vasopressin given 1 h before and at 1, 2 and 3 h after oral administration of 300 mg of the study drug or of placebo. MAIN OUTCOME MEASURE: The area between the recording curve and zero level of pressure. Vital signs, safety parameters and drug plasma concentrations were also measured. RESULTS: The spontaneous uterine activity as well as the response to lysine vasopressin injections before administration of the test drugs were almost identical at the two experiments. Following intake of SR 49059 the area under the recording curve (0-10 min) after the second, third, and fourth injection of lysine vasopressin were reduced by 57, 42, and 66%, respectively, compared with placebo. Trough plasma concentrations of lysine vasopressin were markedly higher and systolic blood pressure slightly lower after antagonist administration than after placebo, whereas no significant difference between treatments was observed in diastolic pressure, heart rate or plasma osmolality. CONCLUSIONS: This study demonstrates for the first time a biological effect of an orally active vasopressin V1a antagonist in humans in vivo and the results support the importance of vasopressin in uterine activation. The differences between study drug and placebo treatments in lysine vasopressin levels and systolic blood pressure, but lack of difference in osmolality indicate that SR 49059 antagonises the effect of lysine vasopressin on the vasopressin V1a receptor, but not that on the vasopressin V2 one. It is suggested that SR 49059 be explored therapeutically in dysmenorrhoea.

Effect of the non-peptide, vasopressin V1a receptor antagonist, SR 49059 and its enantiomer, SR 49770, on isolated human myometrium.

BACKGROUND: Vasopressin seems to be an important etiological factor for the myometrial hyperactivity and reduced blood flow in primary dysmenorrhea. Substances which block the action of vasopressin on the uterus are therefore of interest. METHODS: The effect of an orally active, non-peptide vasopressin V1a receptor antagonist, SR 49059, as well as its enantiomer, SR 49770, which is 50 to 100 fold less potent in binding studies, were tested in vitro on myometrium from 14 subjects. Two doses of the compounds, 2 nmol/L and 10 nmol/L, were used for counteracting the contractile effect of arginine vasopressin in a concentration of 0.7 nmol/L. RESULTS: SR 49059, in the lower concentration, significantly decreased the response to arginine vasopressin, measured as area under the recording curve, to 48 per cent of that to the agonist alone, and in the higher dose to 28 per cent. SR 49770 was much less potent in reducing the response to vasopressin. CONCLUSION: The myometrial action of arginine vasopressin is exerted via V1a receptors. The potent stereospecific inhibitory effect of SR 49059 on arginine vasopressin-induced myometrial activity indicates that the compound acts specifically through V1a receptors and may have a therapeutic potential in primary dysmenorrea.

Receptor-mediated uterine effects of vasopressin and oxytocin in nonpregnant women.

OBJECTIVE: To study in nonpregnant women myometrial actions of vasopressin and oxytocin and the involvement in these effects of specific uterine receptors. SUBJECTS: Twenty-eight women undergoing hysterectomy for benign gynaecological disorders. INTERVENTIONS: Intrauterine pressure recordings. Intravenous bolus injections of 10 pmol/kg body weight of vasopressin and oxytocin. Repeated blood sampling for measurement of vasopressin and oxytocin concentrations in plasma. Recording of effects of vasopressin and oxytocin on isolated myometrium. Estimation of myometrial concentrations of vasopressin V1a and oxytocin receptors. Measurement of plasma oestradiol and progesterone. MAIN OUTCOME MEASURES: Vasopressin- and oxytocin-induced increases of the area under the in vivo recording curve over 10 minutes and EC50 concentrations of dose-responses in vitro. Concentrations of vasopressin V1a and oxytocin receptors. RESULTS: Vasopressin was on average four times more potent than oxytocin in vivo. The effect of vasopressin premenstrually was more pronounced than in women under oestrogen influence only (proliferative phase-hyperproliferation; P = 0.02), and tended to be more marked than in those in the luteal phase (P = 0.07). No significant variation in oxytocin response with the hormonal state was observed. EC50 concentrations of vasopressin were more than 20 times lower than those of oxytocin. The median concentration of the vasopressin V1a receptor was 208 (range 139-343) fmol/mg protein and that of the oxytocin receptor 49 (38-87) fmol/mg protein. Vasopressin receptor concentrations and in vivo effects of this peptide did not correlate, whereas for those of oxytocin a significant correlation was observed (P = 0.02). CONCLUSION: The high potency of vasopressin in nonpregnant women, particularly premenstrually, firmly supports an aetiological importance of this peptide in the uterine hyperactivity of primary dysmenorrhoea. Oxytocin seems to be less important in this condition in view of its much smaller potency and the absence of increase in effect premenstrually. Vasopressin appears to influence both the oxytocin and the vasopressin V1a receptor sites in the uterus, whereas oxytocin acts specifically on its own receptor.

Circulating oxytocin and vasopressin is influenced by ovarian steroid replacement in women.

BACKGROUND: The posterior pituitary hormones appear to be involved in the etiology of primary dysmenorrhoea, but mechanisms regulating their release, particularly the influence of ovarian steroids, are not fully understood. METHODS: The effect of 17 beta-estradiol and medroxyprogesterone alone and in combination on oxytocin and vasopressin levels was therefore studied in 10 postmenopausal women. RESULTS: Transdermal treatment with estradiol alone by means of patches in a dose of 100 micrograms/24 h for five days resulted in an elevation of the mean plasma concentration of this hormone from undetectable to 262 pmol/l and increase in mean circulating levels of vasopressin from 0.82 to 1.22 pmol/l and of oxytocin from 2.50 to 3.98 pmol/l. Oral administration of medroxyprogesterone in a dose of 10 mg per day for 5 days, which resulted in a mean plasma level of 4.3 nmol/l, suppressed vasopressin concentrations to 0.60 pmol/l. When given after five days of treatment with estradiol, medroxyprogesterone also antagonized the stimulatory effect of the estrogen on vasopressin secretion. Medroxyprogesterone alone increased the plasma oxytocin concentration to 3.26 pmol/l, but the progestogen did not significantly influence the stimulatory effect of estradiol on oxytocin secretion. CONCLUSIONS: It is concluded that posterior pituitary hormone secretion is influenced by estradiol and progestogens, and that this may be a mechanism for the involvement of ovarian hormones in the etiology of primary dysmenorrhoea.

Receptors for and myometrial responses to oxytocin and vasopressin in preterm and term human pregnancy: effects of the oxytocin antagonist atosiban.

OBJECTIVE: Our purpose was to study myometrial oxytocin and type V1 vasopressin receptors, the in vitro contractile effects of these hormones, and the influence of an oxytocin antagonist. STUDY DESIGN: Women delivered by cesarean section preterm (n = 51) and at term (n = 71), with and without labor contractions, gave myometrium for the estimation of oxytocin and V1 vasopressin receptors. The in vitro myometrial effects of the peptides and the influence on these of the competitive oxytocin receptor blocking agent 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin were also tested. RESULTS: The median concentration of oxytocin receptors was 116 fmol/mg protein (range 15 to 372 fmol/mg protein) in patients delivered preterm not in labor, 134 fmol/mg protein (27 to 1421 fmol/mg protein) in the beginning of labor, and 46 fmol/mg protein (9 to 140 fmol/mg protein) in advanced labor. At term the corresponding concentrations were 172 (25 to 629), 223 (24 to 414), and 70 (21 to 92) fmol/mg protein. The concentration of V1 vasopressin receptors also decreased in advanced labor. In advanced labor after oxytocin infusion a reduction in the concentration of the receptor for this hormone was observed, which appeared to be related to the duration and dose of treatment. Oxytocin receptors did not vary between women with different indications for cesarean section. The oxytocin effects in vitro and the degree of inhibition by the antagonist of oxytocin responses correlated with the concentration of oxytocin receptors but not with that of V1 vasopressin receptors. No correlation was seen between the response to vasopressin and concentrations of oxytocin or V1 vasopressin receptors. CONCLUSIONS: The effect of oxytocin on the myometrium in pregnancy is mediated by an oxytocin receptor, whereas vasopressin acts on both oxytocin and vasopressin receptors. The initiation of labor both preterm and at term may be primarily related to increased release of oxytocin, which is locally produced in the uterus and not detectable in the plasma, but oxytocin and vasopressin receptors may play a role in the regulation of labor. The analog 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin, which blocks both the oxytocin and the V1 vasopressin receptor, should inhibit labor both preterm and at term, the former confirming results of recent clinical studies in Sweden and the United States.

Plasminogen activators and plasminogen activator inhibitors in blood and tumour fluids of patients with ovarian cancer.

We quantitated urokinase and tissue plasminogen activator (u-PA, t-PA), plasminogen activator inhibitor 1 and 2 (PAI-1, PAI-2), and fibrinolytic activity in peripheral blood (PB), tumour blood (TB), peritoneal/ascitic fluid (PAF) and cystic fluid (CF) from 104 patients with benign and 36 patients with malignant ovarian tumours, and in peripheral blood from 62 healthy controls. PB levels of u-PA were higher in patients with benign and malignant tumours than in controls. High concentrations of u-PA were found in CF, but not in TB, suggesting that u-PA is released by the tumour tissue, but not by the tumour vasculature. PB levels of t-PA were higher in both tumour groups than in controls. Increased levels of t-PA were found in TB, but not in CF, indicating that t-PA is released by the tumour vasculature, but not by the tumour tissue. PB levels of PAI-1 were higher in patients with both benign and malignant tumours than in controls. High levels of PAI-1 were present in both TB and CF from malignant tumours, suggesting that PAI-1 is released from the tumour vasculature as well as the tumour tissue. Elevated concentrations of PAI-2 were found in CF, but not in TB, indicating release from the tumour tissue, but not from the vasculature. High levels of t-PA, PAI-1 and PAI-2 were found in PAF of malignant tumours, and resorption from this compartment may explain elevated PB levels in patients with ascites. None of the PAs/PAIs proved useful as a PB marker for detection of early stage ovarian cancer. However, an index based on PAF levels of t-PA and PAI-1 discriminated between malignant and benign ovarian cysts in the absence of ascites. In addition, our study stresses the importance of including patients with benign tumours as well as healthy controls when markers for malignant tumours are evaluated.