Results from an ultrasound-based familial ovarian cancer screening clinic: a 10-year observational study.

OBJECTIVES: To assess the use of transvaginal sonography as a screening test for familial ovarian cancer and, secondarily, to determine the value of a family history of malignant disease and the potential role of serum CA 125 levels in the screening procedure. METHODS: Two thousand five hundred self-referred women were studied at the Ovarian Screening Clinic at King's College Hospital, London. These symptom-free women with at least one close relative who had developed ovarian cancer were studied prospectively. Each woman was scanned for the presence of a persistent ovarian lesion and a sample of peripheral blood was taken for the retrospective analysis of serum CA 125. Women with a positive screen result were referred for surgical investigations; those with a negative result but considered to be at high risk were rescreened. The main outcome measures were findings at surgery, the histological classification of ovarian lesions, and cancer reported at follow-up. RESULTS: The women were aged 17 to 78 (mean, 48) years; 65% were premenopausal, 26% were postmenopausal and 9% had undergone hysterectomy. Seven hundred and thirty-eight women (29.5%) had a family history of multiple site cancers and 279 (11.2%) reported cancer specific to the ovary. There were 4231 screenings (2500 first screens, 998 second screens and 733 third or higher order screens). One hundred and four screens gave a positive result (2.5%); 11 cancers were detected (seven (64%) at stage I, four of which were of borderline malignancy). One additional cancer was reported within 12 months of the last scan and classified as a false-negative screen result. Eight cancers (including two peritoneal) were reported at follow-up (> 1-9 years after the last scan). All these women presented at an advanced stage (stage III). Fifteen of 20 cancers occurred in premenopausal women. The overall sensitivity of ultrasound screening was 92% (95% confidence interval, 76-100); the specificity was 97.8%. The prior odds of any woman having a screen-detectable ovarian malignancy during the study period were 1 : 207. The posterior odds subsequent to a positive screen result were 1 : 8.5 (1 : 12.7 at Screen 1; 1 : 3.7 at Screen 2; 1 : 3.0 at subsequent screens); the value was 1 : 11.4 for women with one family relative with ovarian cancer and 1 : 5.0 for women with the site-specific ovarian cancer syndrome. The prior use of a decision level for serum CA 125 >or= 20 U/mL would have reduced the number of women undergoing sonography by 78%; seven of the 12 cancers (58%) would have been detected (63% of all stage I disease, 75% of invasive stage I disease). An alternative cut-off value of 35 U/mL would have resulted in a detection rate of 33%. CONCLUSIONS: Transvaginal sonography can effectively detect intraovarian cancer and tumors of borderline malignancy in women with a family history of the disease. Screening efficacy is related to the type of family history. The level of serum CA 125 can be used to select women for sonography, but the detection rate for early cancers would be reduced.

Effects of indomethacin on follicular structure, vascularity, and function over the periovulatory period in women.

OBJECTIVE: To assess the effect of indomethacin (taken at defined times) on follicular rupture, indexes of intrafollicular blood flow, and steroidogenesis. PARTICIPANTS: Six healthy volunteers awaiting treatment for infertility by IVF-ET during subsequent natural cycles. INTERVENTIONS: All women were examined (at least every 8 hours) by transvaginal ultrasonography with color Doppler imaging and had samples of blood taken for hormone analysis. A self-test for urinary LH was performed before each scan. Indomethacin was first taken (50 mg three times per day) according to the maximum follicular diameter (first four women) or when the LH dipstick gave a positive result; the drug was taken for > or = 3 days. RESULTS: Follicular rupture was delayed in five of six cases (by 2 to 12 days). There was a reduction in intrafollicular peak systolic velocity before and after the positive urinary LH test compared with historical controls. Three follicles (50% of women) with the highest peak systolic velocity had an hemorrhagic appearance and persisted longer. There was no significant effect on menstrual cycle length or the levels of circulating FSH, E2, LH, or P. CONCLUSION: Indomethacin administered at the time of a positive self-test for urinary LH can delay follicular rupture with an associated reduction in intrafollicular blood flow but with no apparent effects on hormonal or menstrual status.

Circadian variation in uterine artery blood flow indices during the follicular phase of the menstrual cycle.

We investigated for the presence of circadian variation in uterine artery blood flow indices during the late follicular phase of the menstrual cycle. Twenty women with regular menstrual cycles underwent transvaginal color Doppler assessment of blood flow in the uterine arteries on two occasions precisely 12 h apart on the same day in the follicular phase. Ultrasound examinations were performed between 06.00 and 10.00 and repeated between 18.00 and 22.00. Indices of uterine artery blood flow included the pulsatility index (PI) and the time-averaged maximum velocity (TAMX). The changes in PI and TAMX were related to variations in serum concentrations of estradiol and luteinizing hormone (LH). We noted a significantly higher PI and lower TAMX in the evening compared to the morning values, p < 0.001 and p = 0.01, respectively. There was no significant change in estradiol or LH concentrations between morning and evening (p > 0.05). There appears to be a circadian rhythm in uterine artery blood flow occurring independently of these hormonal parameters. The circadian changes in PI and TAMX may be larger than the previously described effects of hormones on these parameters. The accurate interpretation of uterine artery blood flow indices should take these time-related fluctuations into account.

Transvaginal color blood flow imaging of the periovulatory follicle.

OBJECTIVE: To assess intrafollicular blood flow in relation to ovarian morphology and function during the periovulatory period. DESIGN: A prospective, longitudinal study of random, natural ovarian cycles. SETTING: The Ovarian Screening Clinic and Endocrine Laboratory of the Department of Obstetrics and Gynaecology, King's College Hospital, London, United Kingdom. PATIENTS: Women with apparently normal ovarian function awaiting treatment for infertility by IVF-ET during subsequent natural cycles. INTERVENTIONS: All women were examined by transvaginal ultrasonography with color flow imaging and had a sample of peripheral venous blood taken at each scan for hormone analysis. MAIN OUTCOME MEASURES: The minimum pulsatility index (PI) and maximum peak systolic velocity from vessels within the dominant follicle; the maximum follicular diameters (and hence volume); serum FSH, E2, LH, and P. RESULTS: The dominant follicle ruptured in 10 of 11 women. The median interval between the two scans that delineated the time of follicular rupture was 9.5 hours (range, 0.0 to 24.5 hours). These cycles appeared to be morphologically and endocrinologically normal. There was an apparent increase in intrafollicular blood flow over the periovulatory period with an insignificant trend toward lower values for the mean PI and a significant increase in the peak systolic velocity. These changes appeared to follow the rise in circulating LH. CONCLUSION: Indexes of blood flow at a given site within the leading follicle can be monitored by transvaginal ultrasonography with color Doppler imaging over the periovulatory period. The increase in the peak systolic velocity and the relatively constant PI suggest a marked increase in blood flow at this time during the ovarian cycle.

Paracetamol-associated luteinized unruptured follicle syndrome: effect on intrafollicular blood flow.

We are using transvaginal ultrasonography with color Doppler imaging to study changes in intrafollicular blood flow over the periovulatory period. We report here the findings from one volunteer (subject 9), who took two tablets of paracetamol (1000 mg) twice daily (between 07.00 and 08.00, and 18.00 and 19.00) for 2 consecutive menstrual cycle days (12 and 13) to alleviate a headache, which was shown retrospectively to have occurred within the duration of the luteinizing hormone (LH) surge in peripheral plasma. The drug appeared to have a profound effect on peak systolic blood velocity within the preovulatory follicle. Color (an index of blood velocity) disappeared and flow velocity waveforms were not detectable for at least 4 h. Color then re-appeared, but the peak systolic blood velocity had reduced by 69.8% (from 18.2 to 5.5 cm/s). The peak systolic blood velocity recovered subsequently to 16.3 cm/s, but the follicle did not rupture and continued to grow to a maximum diameter > 59 mm. There was no apparent effect of the drug on expected changes in the circulating levels of estradiol, LH, follicle stimulating hormone or progesterone. The secretory phase of the menstrual cycle lasted 13 days (i. e. day of LH peak to day of next menses minus one). We suggest that paracetamol taken at the time of the LH surge may affect intrafollicular peak systolic blood velocity and might inhibit ovulation. Possible molecular mechanisms are discussed.

The effect of human chorionic gonadotropin and pregnancy on the circulating level of relaxin.

The effect of hCG and pregnancy on the circulating levels of relaxin was investigated in 48 women undergoing in vitro fertilization and embryo transfer (ET) for the treatment of infertility. Subjects were allocated randomly to receive hCG (Profasi; 2000 IU, im) or placebo on the day of ET (day 0) and on day 3 after ET (day 3). Samples of peripheral blood were taken on days -4, 6, and 10. An additional sample was taken on day 22 from women who became pregnant. The subjects were allocated retrospectively to 1 of 4 groups: no pregnancy, no hCG (NP); pregnancy, no hCG (P); no pregnancy, hCG (NPH); and pregnancy, hCG (PH). Two patients with blighted ova and one with a tubal pregnancy were excluded from the analysis. The concentrations of relaxin were similar and rose significantly in all groups at each time point (P less than 0.05). On day 6 there was no significant difference in the increment between the groups, but by day 10, circulating levels in the P compared to the NP and those in the PH compared to the NPH group were significantly greater (P less than 0.05). By day 22 the difference between the PH and the P groups was significant (P less than 0.05). Relaxin levels correlated with progesterone levels on day 10 in the NP and P groups (r = 0.633; P less than 0.05 and r = 0.697; P less than 0.05, respectively) and with estradiol levels in the P group only on days 6 and 22 (r = 0.659; P less than 0.05 and r = 0.783; P less than 0.05, respectively). These data demonstrate that in women undergoing in vitro fertilization, relaxin levels increase during the luteal phase, and in those women who establish a pregnancy, the values are significantly greater by day 10. The administration of hCG in the early luteal phase, before implantation, to women who subsequently become pregnant significantly increased the level of circulating relaxin on day 22. The positive correlation between relaxin levels and ovarian steroid levels in the groups not receiving exogenous hCG suggests that a common factor may control the release of both.