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.

Benign ovarian cysts and ovarian cancer: a cohort study with implications for screening.

BACKGROUND: Whether some benign ovarian cysts can develop into cancerous cysts is not known. If a large proportion of ovarian cancers arose in this way, it might be possible to remove the benign cysts in a screening programme before they became malignant. We used follow-up data from a cohort of 5479 self-referred women without symptoms, who participated in a ultrasonographic-screening trial for early ovarian cancer between June, 1981, and August, 1987. We assessed whether the removal of persistent ovarian cysts from these women was associated with a reduction in the expected number of deaths from ovarian cancer in the cohort as a whole. METHODS: The expected number of deaths from all causes, all cancers, and ovarian, breast, and colorectal cancers were calculated for the study cohort by the standard life-table method. The actual number of deaths and each cause were obtained and the proportional mortality ratio was calculated for each cause of death. FINDINGS: 5135 (95%) of the participants in the original trial were traced. During the screening, five of these women were found to have stage I epithelial ovarian cancer and 88 had benign epithelial ovarian tumours. The number of reported deaths from all causes (387 [50% of expected]), all cancers (221 [71%]), and ovarian cancer (22 [90%]) was lower than expected because of the "healthy-volunteer effect". Proportional mortality ratios were 100% (by definition) for all cancers, 141% for breast cancer, 128% for ovarian cancer (95% CI 87.7-187.6, p=0.19), 84% for colorectal cancer, and 48% for lung cancer. INTERPRETATION: The removal of persistent ovarian cysts was not associated with a decrease in the proportion of expected deaths from ovarian cancer relative to other cancers during follow-up. For population-based screening of healthy women without a family history of ovarian cancer, a screening test is required that is specific and sensitive to early malignant disease, and inexpensive.

A comparison of methods for preoperative discrimination between malignant and benign adnexal masses: the development of a new logistic regression model.

OBJECTIVE: The aim of this study was to assess the complementary use of ultrasonographic end points with the level of circulating CA 125 antigen by multivariate logistic regression analysis algorithms to distinguish malignant from benign adnexal masses before operation. STUDY DESIGN: One hundred ninety-one patients aged 18 to 93 years with overt adnexal masses were examined by transvaginal ultrasonography with color Doppler imaging and 31 variables were recorded. The end points were the histologic classification of the tumor and the areas under the receiver-operator characteristic curves of alternative algorithms. RESULTS: One hundred forty patients had benign tumors and 51 (26.7%) had malignant tumors: 31 primary invasive tumors (37% International Federation of Gynecology and Obstetrics stage I), 5 tumors of borderline malignancy (100% International Federation of Gynecology and Obstetrics stage I), and 15 tumors were metastatic and invasive. The most useful variables for the logistic regression analysis were the menopausal status, the serum CA 125 level, the presence of >/=1 papillary growth (>3 mm in length), and a color score indicative of tumor vascularity and blood flow. The optimized procedure had a sensitivity of 95.9% and a specificity of 87.1%. The area under the receiver-operator characteristic curve was significantly higher (P <.01) than the corresponding values from the independent use of serum CA 125 levels or indexes of tumor form or vascularity. CONCLUSION: Regression analysis of a few complementary variables can be used to accurately discriminate between malignant and benign adnexal masses before operation.

Sonographic prediction of malignancy in adnexal masses using an artificial neural network.

OBJECTIVE: To generate a neural network algorithm which computes a probability of malignancy score for pre-operative discrimination between malignant and benign adnexal tumours. DESIGN: A retrospective analysis of previously collected data. Information from 75% of the study group was used to train an artificial neural network and the remainder was used for validation. SETTING: The Gynaecological Ultrasound Research Unit at King's College Hospital, London. POPULATION: Sixty-seven women with known adnexal mass who had been examined using transvaginal B-mode ultrasonography and colour Doppler imaging with pulse spectral analysis immediately before surgery. The excised masses were classified histologically as benign (n = 52) or malignant (n = 15), of which three were borderline. METHODS: The variables that were put into the artificial neural network were: age, menopausal status, maximum tumour diameter, tumour volume, locularity, the presence of papillary projections, the presence of random echogenicity, the presence of analysable blood flow velocity waveforms, the peak systolic velocity, time-averaged maximum velocity, the pulsatility index, and resistance index. Histological classification, categorised as benign or malignant, was the output result. RESULTS: A variant of the back propagation method was selected to train the network. The overall architecture of the network with the best performance contained an input layer with four variables (age, time-averaged maximum velocity, papillary projection score and maximum tumour diameter), a hidden layer with three units and an output layer with one. The sensitivity and specificity at the optimum diagnostic decision value for the artificial neural network output (0.45) were 100% (95% CI 78.2%-100%) and 98.1% (95% CI 89.5%-100%), respectively. These values were significantly better than those obtained from the independent use of the resistance index, pulsatility index, time-averaged maximum velocity or peak systolic velocity at their optimum decision values (P < 0.01). CONCLUSION: Artificial neural networks may be used on clinical and ultrasound derived end-points to accurately predict ovarian malignancy. There is a need for a prospective evaluation of this technique using a larger number of patients.

Subjective assessment of adnexal masses with the use of ultrasonography: an analysis of interobserver variability and experience.

OBJECTIVE: The aim of the study was to evaluate the subjective assessment of ultrasonographic images for discriminating between malignant and benign adnexal masses. STUDY DESIGN: The study was prospective. Initially, one ultrasonographer preoperatively assessed 300 consecutive patients with adnexal masses. Subsequently, the recorded transparent photographic prints were independently assessed by five investigators, with different qualifications and level of experience, who were also given a brief clinical history of the patients (i.e. the age, menstrual status, family history of ovarian cancer, previous pelvic surgery and the presenting symptoms). The diagnostic performance of the observers was compared with the histopathology classification of malignant or benign tumors. The end-points were accuracy, interobserver agreement and the possible effect of experience. RESULTS: The first ultrasonographer and the most experienced investigator both obtained an accuracy of 92%. There was very good agreement between these two investigators in the classification of the adnexal masses (Cohen's kappa 0.85). The less experienced observers obtained a significantly lower accuracy, which varied between 82% and 87%. Their interobserver agreement was moderate to good (Cohen's kappa 0.52 to 0.76). CONCLUSION: Experienced ultrasonographers using some clinical information and their subjective assessment of ultrasonographic images can differentiate malignant from benign masses in most cases. The accuracy and the level of interobserver agreement are both correlated with experience. About 10% of masses were extremely difficult to classify (only < 50% of assessors were correct).

Artificial neural network models for the preoperative discrimination between malignant and benign adnexal masses.

OBJECTIVE: The aim of this study was to generate and evaluate artificial neural network (ANN) models from simple clinical and ultrasound-derived criteria to predict whether or not an adnexal mass will have histological evidence of malignancy. DESIGN: The data were collected prospectively from 173 consecutive patients who were scheduled to undergo surgical investigations at the University Hospitals, Leuven, between August 1994 and August 1996. The outcome measure was the histological classification of excised tissues as malignant (including borderline) or benign. METHODS: Age, menopausal status and serum CA 125 levels and sonographic features of the adnexal mass were encoded as variables. The ANNs were trained on a randomly selected set of 116 patient records and tested on the remainder (n = 57). The performance of each model was evaluated using receiver operating characteristic (ROC) curves and compared with corresponding data from an established risk of malignancy index (RMI) and a logistic regression model. RESULTS: There were 124 benign masses, five of borderline malignancy and 44 invasive cancers (of which 29% were metastatic); 37% of patients with a malignant or borderline tumor had stage I disease. The best ANN gave an area under the ROC curve of 0.979 for the whole dataset, a sensitivity of 95.9% and specificity of 93.5%. The corresponding values for the RMI were 0.882, 67.3% and 91.1%, and for the logistic regression model 0.956, 95.9% and 85.5%, respectively. CONCLUSION: An ANN can be trained to provide clinically accurate information, on whether or not an adnexal mass is malignant, from the patient's menopausal status, serum CA 125 levels, and some simple ultrasonographic criteria.

Thymidine phosphorylase activity and prodrug effects in a three-dimensional model of angiogenesis: implications for the treatment of ovarian cancer.

Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is associated with angiogenesis and the progression of human ovarian cancer. The enzyme converts thymidine to thymine and 2'-deoxyribose-1-phosphate and can also metabolize the prodrug 5'-deoxy-5-fluorouridine (Furtulon) to 5-fluorouracil and 5'-deoxy-D-ribose-1-phosphate. The aim of this study was to obtain information about the activities of Furtulon in an established three-dimensional model of angiogenesis. The plan was to study partial and complete effects of Furtulon (in the absence and presence of PD-ECGF/TP or ovarian cancer cyst fluids) on the formation and destruction of microvessels from cultured segments of rat aorta in serum-free media. The endpoint was the number and form of microvessels compared with controls after 4, 7, 11, and 14 (and sometimes 17) days in culture. Furtulon (10 micromol/L) gradually reduced the size and number of microvessels over 17 days of culture (100 micromol/L significantly reduced the number by day 4). PD-ECGF/TP (10 ng/ml) and ovarian cancer cyst fluids (2% in medium, v/v) stimulated the production of microvessels. The culture of explants with Furtulon and PD-ECGF/TP or ovarian cancer cyst fluids (from day 1 or day 11 of culture) enhanced the vasoclastic activity of the drug. The effect of Furtulon at the highest dose (1000 micromol/L) or at a lower dose (100 micromol/L) in the presence of ovarian cancer cyst fluid was not reversible after culture day 11.

Expression of thymidine phosphorylase in malignant ovarian tumors: correlation with microvessel density and an ultrasound-derived index of angiogenesis.

OBJECTIVE: The aim of this study was to determine whether the expression of thymidine phosphorylase by ovarian cancer cells correlates with the density of microvessels within the tumor, and with ultrasound-derived indices of blood flow. METHODS: Transvaginal ultrasonography with color Doppler imaging and pulsed Doppler spectral analysis was used to scan patients with an overt ovarian mass immediately before laparotomy. Sections of malignant tumors were analyzed for the cellular expression of thymidine phosphorylase and the intratumoral density of microvessels by immunohistochemistry using monoclonal antibodies to thymidine phosphorylase and factor VIII-related antigen, respectively. The main outcome measures were the histological classification of the tumor, the stage of the disease, whether or not the tumor cells were positive or negative for thymidine phosphorylase, the microvessel count and the peak systolic velocity (PSV). RESULTS: Forty-two tumors were studied (three of low malignant potential, 29 epithelial, four granulosa cell, two germ cell and four metastatic); 18 were stage I, six stage II, 11 stage III and three stage IV. Twenty-seven tumors (64%) were classified as thymidine phosphorylase-positive. The proportion of stage I tumors that was thymidine phosphorylase-positive (44%) was significantly lower (p = 0.022) than the corresponding value for stages II-IV (85%), but the values for microvessel count and PSV were similar. The microvessel count in thymidine phosphorylase-positive tumors was significantly higher than in thymidine phosphorylase-negative tumors (p = 0.005). Similarly, the PSV was significantly higher in thymidine phosphorylase-positive tumors (p = 0.009). There was a significant correlation between the microvessel count and the PSV (r = 0.354, p = 0.022). CONCLUSIONS: The expression of thymidine phosphorylase by malignant tumor cells is associated with an increase in microvessel density and PSV in patients with ovarian cancer.

A randomized trial on the use of ultrasonography or office hysteroscopy for endometrial assessment in postmenopausal patients with breast cancer who were treated with tamoxifen.

OBJECTIVE: Our purpose was to compare the screening effectiveness and acceptability of transvaginal ultrasonography (with sonohysterography if endometrial thickness was >4 mm) with office hysteroscopy. STUDY DESIGN: This randomized crossover study comprised 53 consecutive asymptomatic (without vaginal bleeding) postmenopausal patients with breast cancer who had taken tamoxifen (20 or 40 mg/day) for at least 6 months. RESULTS: Two patients had endometrial cancer (1 primary, 1 breast secondary), both detected only by transvaginal ultrasonography. Twenty-six patients had at least 1 polyp (total 47, all benign). The women who had polyps were not significantly different in their age, body mass, months of tamoxifen intake, or the cumulative dose. The sensitivity and specificity of transvaginal ultrasonography were 85% and 100%, respectively. The corresponding values for office hysteroscopy were 77% and 92%. It was significant that more patients preferred transvaginal ultrasonography to hysteroscopy (P < .001). CONCLUSION: Transvaginal ultrasonography (plus sonohysterography) may be more effective and acceptable than office hysteroscopy for detecting endometrial abnormalities in women taking tamoxifen.

Acute effects of a transdermal nitric oxide donor on perifollicular and intrauterine blood flow.

BACKGROUND: Nitric oxide is a potent vasodilator and is involved in several physiological events during the female reproductive cycle. OBJECTIVE: The aim of this study was to determine the acute effects of a nitric oxide donor on ultrasound-derived indices of blood flow in the intact human uterus and ovaries during the follicular phase of the normal menstrual cycle. STUDY DESIGN: The plan was to perform an observational study of six healthy volunteers, recruited during days 9-12 from day 1 of the last menstruation. Subjects were scanned transvaginally, with B-mode and color Doppler imaging around 12.00, and 2 h after the application of a transdermal glyceryl trinitrate (GTN) patch 10 mg/24 h. The patch was then removed and the subjects were rescanned 2 h later. END-POINTS: The main outcome measures were the peak systolic velocity (PSV), time-averaged maximum velocity (TAMV) and the pulsatility index (PI) derived from flow velocity waveforms, in the left and right main uterine arteries, a radial artery and subendometrial vessels, and from vessels at the rim of the dominant ovarian follicle. RESULTS: One woman was scanned on day 9, two on day 10 and three on day 12 of the cycle. The median pretreatment values for endometrial thickness and follicular volumes were 7.2 mm (range 6.0-10.0 mm) and 3.1 ml (range 0.3-6.8 ml), respectively. GTN induced a significant (p < 0.05) increase in the PSV and TAMV in the subendometrial vessels in all subjects. There was a corresponding decrease in the PI in four cases. Changes in blood flow were reversible (50% of the changes in PSV, TAMV and PI were essentially reversed 2 h after the patch had been removed). In the uterine arteries, PSV and TAMV were significantly (p < 0.01) and progressively decreased with a concomitant significant (p < 0.01) increase in PI. There was also a tendency for the mean PI to decrease progressively in the vessels at the rim of the dominant follicle with decreased post-treatment values in four out of six subjects. CONCLUSIONS: GTN induces a reversible increase in subendometrial blood flow velocity during days 9-12 of the menstrual cycle. The expected circadian decrease in uterine artery blood flow seemed to be partly interrupted by GTN treatment. IMPLICATIONS: These data justify the implementation of randomized controlled studies to determine the potential beneficial effects of transdermal GTN on ovarian and uterine blood flow and function.

An evaluation of sonohysterography and diagnostic hysteroscopy for the assessment of intrauterine pathology.

The availability of advanced hysteroscopic surgical techniques has changed the management of abnormal uterine bleeding. The aim of this study was to evaluate the use of transvaginal sonography (TVS), sonohysterography (SH) and diagnostic hysteroscopy (DH) for the preoperative assessment of the uterine cavity. The plan was to investigate 100 patients with abnormal uterine bleeding despite conventional medical treatment. The endpoints were uterine abnormalities detected by operative hysteroscopy and histology, and subjective estimates of discomfort during TVS and SH. A total of 104 patients (aged 26-79 years) were recruited and 98 (94%) underwent all three diagnostic procedures. Uterine abnormalities were present in 52 patients (53%). There were 25 cases with at least one endometrial polyp, 17 with submucous fibroids, seven with endometrial hyperplasia and three with an adenocarcinoma. The overall sensitivity of TVS improved after SH from 67 to 87% and the specificity from 89 to 91%. The positive predictive value increased from 88 to 92% and the negative predictive value from 71 to 86%. The use of SH also improved the quality of information about the location and size of polyps and submucous fibroids. Increased endometrial thickness associated with adenocarcinoma was detected in all cases (three of three) by TVS and in four of seven cases of hyperplasia (five of seven cases after SH). Most patients reported minor discomfort during TVS or SH and no side-effects were apparent. The sensitivity of DH was 90% (92% for polyps, 88% for fibroids); two cases with a polyp, two with a submucous fibroid and one with endometrial hyperplasia were not detected. The use of saline infusion to enhance visualization of the endometrium increases the diagnostic accuracy of transvaginal sonography to approach that of diagnostic hysteroscopy and also provides some additional information. This development has implications for the management of uterine bleeding disorders.

Effects of platelet-derived endothelial cell growth factor/thymidine phosphorylase, substrate, and products in a three-dimensional model of angiogenesis.

Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is associated with angiogenesis and the progression of human breast and ovarian cancers. The aim of this study was to obtain information about the possible mechanisms of PD-ECGF/TP activity in an established three-dimensional model of angiogenesis. The plan was to study the effects of the enzyme, substrate, products, and further metabolites on the formation and rate of microvessel growth from cultured segments of rat aorta in serum-free media. The end-points were the number and length of microvessels compared with controls after 4, 7, 11, and 14 days in culture. Thymidine (10 to 1000 mumol/L), thymidine-5'-monophosphate (1000 mumol/L), and 2'-deoxy-D-ribose-1-phosphate (1000 mumol/L) inhibited the number of microvessels produced. Conversely PD-ECGF/TP (50 to 100 ng/ml) and beta-amino-iso-butyric acid (1000 mumol/L--a metabolite of thymine) had a significant stimulatory effect (P < 0.05, P < 0.01, P < 0.001 respectively on culture day 11). PD-ECGF (10 ng/ml), beta-amino-iso-butyric acid (1000 mumol/L), and 2-deoxy-D-ribose (100 to 1000 mumol/L) significantly (P < 0.001, P < 0.01, P < 0.01, respectively) stimulated microvessel elongation by day 11. We conclude that PD-ECGF/TP may affect angiogenesis by changing the relative concentrations of pyrimidine-based compounds and their metabolites in interstitial fluid surrounding endothelial cells. Drugs that inhibit PD-ECGF/TP activity may therefore delay abnormal angiogenesis and the progression of various cancers.

Comparison of transvaginal color Doppler imaging and color Doppler energy for assessment of intraovarian blood flow.

OBJECTIVE: To investigate any systematic differences in the analysis of blood flow velocity waveforms derived by color Doppler imaging and color Doppler energy examination of corpora lutea and adnexal tumors, to test whether the accuracy for diagnosing ovarian malignancy differs between end points derived by color Doppler imaging and color Doppler energy, and to compare the reproducibility of flow velocity waveform analysis obtained by both methods. METHODS: Fifty-six asymptomatic women with presumed corpora lutea and 67 women with known adnexal masses were included in the study. They all were examined using transvaginal sonography with color Doppler imaging and color Doppler energy. Pulsed Doppler sonography was used to obtain flow velocity waveforms to determine the pulsatility index (PI), resistance index (RI), peak systolic velocity, and time-averaged maximum velocity. The tumors were classified retrospectively according to histologic criteria. RESULTS: There were 52 women with benign, three with borderline, and 12 with malignant ovarian tumors. Repeated-measures analysis of variance revealed no systematic differences in the values of all four measurements performed under color Doppler imaging and color Doppler energy for all cases of corpora lutea and adnexal tumors (PI: P=.153, RI: P=.197, peak systolic velocity: P=.355, time-averaged maximum velocity: P=.159). All cases of borderline and malignant tumors had detectable pulsatile blood flow with color Doppler imaging and color Doppler energy. Forty-two (80.8%) of the benign tumors had flow detectable with color Doppler imaging, compared with 40 (76.9%) with color Doppler energy (P=.480). Analysis of receiver operating characteristic curves showed a marginal but nonsignificant improvement in diagnostic performance with color Doppler energy compared with color Doppler imaging for all four measurements (PI: P=.182, RI: P=.178, peak systolic velocity: P=.254, time-averaged maximum velocity: P=.238). The intraclass correlation coefficients for all four measurements were superior with color Doppler imaging compared with color Doppler energy. CONCLUSION: Flow velocity waveform analysis and diagnostic accuracy for ovarian malignancy are not significantly different between color Doppler imaging and color Doppler energy. Examinations with color Doppler imaging appear to be more reproducible than those with color Doppler energy.

Preovulatory changes of blood flow in different regions of the human follicle.

OBJECTIVE: To assess regional changes in ultrasound-derived indices of blood flow in the dominant human follicle after the plasma LH surge. DESIGN: A cross-sectional, prospective study. SETTING: Reproductive medicine unit at a university. PATIENT(S): Women attending an assisted conception clinic to determine the appropriate time to transfer previously frozen embryos during a natural cycle. INTERVENTION(S): Transvaginal ultrasonography with color Doppler imaging and pulsed Doppler spectral analysis was used to obtain indices of blood flow and velocity from vessels in the base, lateral part, and apex of the dominant follicle on days 10-12 (from day 1 of menses) and after the LH surge, but before rupture. Immunoassays were used to measure the blood concentrations of LH twice daily (at 8-10 A.M. and 4-6 P.M.) from cycle day 10. MAIN OUTCOME MEASURE(S): The pulsatility index (PI), resistance index (RI), peak systolic velocity (PSV), and time-averaged maximum velocity (TAMXV) in the uterine arteries and three regions of the dominant follicle (apical, lateral, and basal parts); follicular volume; the day and time of the onset of the LH surge (defined as first concentration of LH > 22 U/L) and the times of each scan. RESULT(S): Twenty-two women (aged 28-39 years) were studied and seven were scanned on days 10-12. A retrospective examination of the data from the remainder showed that eight were scanned < 20 hours after onset of the LH surge and seven were scanned > 20 hours after the onset of the LH surge. There was a significant increase in follicular volume after the LH surge. The PI was similar in vessels from the base (0.86 +/- 0.11; mean +/- SEM), lateral part (0.72 +/- 0.51) and apex (0.67 +/- 0.09) at cycle days 10-12 and then gradually decreased in the apex. There were similar changes in the RI. The PSV (mean +/- SEM; cm/s) was similar in vessels from the base (10.1 +/- 1.64), lateral side (8.2 +/- 1.43), and apex (9.2 +/- 1.91) in follicles of days 10-12. Within 20 hours of the onset of the LH surge, the PSV had increased in basal vessels (23.4 +/- 4.10), remained similar in lateral vessels (11.64 +/- 3.18), and was undetectable in apex vessels from six of eight follicles. Twenty hours after the LH surge, there was no pulsatile blood flow observed in the apical part of the follicle, but there was a sustained high PSV in the base (15.73 +/- 3.42) and lateral side (9.02 +/- 1.5). There were corresponding changes in the TAMXV. CONCLUSION(S): During the ovulatory process there are prominent changes in the regional blood flow of the follicle with a marked increase of the flow to the base of the follicle and a concomitant decrease of blood flow to the apex. These changes may be essential for the release of a mature oocyte.

Screening strategies for ovarian cancer.

Alternative procedures have been proposed for the detection of early ovarian cancer in asymptomatic women. Transvaginal ultrasonography, with or without colour Doppler imaging and intra-tumoural blood flow analysis, is used as the definitive technique in all current screening programmes. Target populations for clinical trials are recruited on the basis of risk factors for the disease (e.g. age or postmenopausal status, family history of ovarian cancer). Whether or not a participant is scanned may depend on results from the immunoassay of tumour antigens in peripheral serum, or from pedigree analysis. New developments include the use of: (i) intra-tumoural blood velocity as an end-point of colour Doppler imaging, (ii) serial measurements of serum tumour antigens to identify women for ultrasonography, and (iii) tests which detect regionally clustered germ-line BRCA1 mutations. More research is required to assess the beneficial and adverse effects of the new strategies.

Randomized, double-blind, dose-ranging study of the endometrial effects of a vaginal progesterone gel in estrogen-treated postmenopausal women.

OBJECTIVE: Our purpose was to assess the endometrial effects of two doses of natural progesterone administered by a bioadhesive vaginal gel in estrogen-treated postmenopausal women. STUDY DESIGN: This was a double-blind, randomized, dose-ranging study of 31 postmenopausal women attending a specialist menopause clinic. Endometrial histologic features, sex steroid hormone concentrations, and vaginal bleeding patterns were assessed during three 28-day cycles of continuous oral conjugated estrogens (0.625 mg/day) and two doses of sequential vaginally administered natural progesterone (45 or 90 mg every 48 hours). Histologic results are presented descriptively. Between-group comparisons of other parameters were made with the use of the Mann-Whitney U and Student t tests. RESULTS: Secretory endometrium was found in 35 of 41 histologic samples that yielded adequate tissue for diagnosis. There was one case of proliferative endometrium in the 45 mg progesterone group and none in the 90 mg group and no cases of hyperplasia. Mean plasma progesterone concentrations of 4.6 ng/ml and 6.8 ng/ml were achieved in the 45 and 90 mg groups, respectively. CONCLUSIONS: Very low doses of natural progesterone, when administered vaginally in a bioadhesive gel, cause secretory endometrial transformation in estrogen-treated postmenopausal women.