Thomas H. Bourne

Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial

Randomised, double-blind controlled trials have been started to determine whether tamoxifen can prevent or delay development of breast cancer in healthy women with a family history of the disease. We recruited a randomised cohort of 111 postmenopausal women (aged 46-71 years) from the Pilot Breast Cancer Prevention Trial at the Royal Marsden Hospital to study the effect of tamoxifen on the uterus and ovaries. The main outcome measures were obtained by transvaginal ultrasonography with colour doppler imaging and microscopic examination of endometrial biopsies removed at the time of the scan. There was no significant difference between tamoxifen (20 mg/day) and placebo groups in the age of the women, or the time of the scan (and sampling) after randomisation. Women taking tamoxifen had a significantly larger uterus and a lower impedance to blood flow in the uterine arteries. 39% of women taking tamoxifen had histological evidence of an abnormal endometrium compared with 10% in the control group. 10 patients in the tamoxifen group (16%) had atypical hyperplasia and another 5 (8%) had a polyp. Women with a histological abnormality had a significantly thicker endometrium and a decreased impedance to blood flow in the uterine arteries. There was no correlation between the presence of uterine abnormalities and the age of the women, or the concentrations of tamoxifen or desmethyl tamoxifen in the peripheral blood. These findings confirm that tamoxifen can cause potentially malignant changes in the endometrium of postmenopausal women. Transvaginal ultrasonography can be used to identify those women who should have endometrial samples removed for microscopic analysis.

Transvaginal colour flow imaging: a possible new screening technique for ovarian cancer.

OBJECTIVE--To assess whether changes in the intraovarian vasculature or blood flow impedance can be used to identify potentially malignant masses. DESIGN--Open, non-comparative prospective study. SETTING--Ovarian screening clinics at Kings College Hospital and the Hallam Medical Centre. SUBJECTS--50 Women selected on the basis of their medical history and the result of a previous transvaginal ultrasound scan. Thirty women (10 premenopausal (scan taken on days 1 to 8 of the menstrual cycle) and 20 postmenopausal) had normal ovaries, and 20 had at least one ovary with an abnormal morphology or volume, or both. INTERVENTIONS--Women with a positive result on screening were referred for laparotomy. MAIN OUTCOME MEASURES--Presence or absence of coloured areas (neovascularisation) and the pulsatility index within each ovary. The pulsatility index is a measure of the impedance to blood flow, a low value indicating decreased impedance and a high value increased impedance to blood flow. RESULTS--Two women with a positive result on screening had hydrosalpinges, 10 a benign tumour or a tumour-like condition, and eight primary ovarian cancers. No areas of neovascularisation were seen in the 30 women with morphologically normal ovaries and the two patients with hydrosalpinges; the pulsatility index ranged from 3.1 to 9.4. Similarly, nine patients (10 affected ovaries) with a non-malignant mass had no signs of neovascularisation and the pulsatility index varied from 3.2 to 7.0. One patient with bilateral dermoid cysts containing nests of thyroid-like cells had vascular changes and pulsatility index values of 0.4 and 0.8. Seven patients (eight ovaries) with primary ovarian cancer (one stage IV, four stage II, and two stage Ia) showed clear evidence of neovascularisation and pulsatility index values were from 0.3 to 1.0. One patient with an intraepithelial serous cystadenocarcinoma in a small ovary (less than 5 ml volume) had no signs of any vascular change and the pulsatility index was 5.5. CONCLUSION--Transvaginal colour flow imaging may be used to identify potentially malignant ovarian masses and help elucidate the early stages of tumorigenesis. The routine application of this technique may reduce the rate of false positive results of an ultrasonography based screening procedure.

Screening for early familial ovarian cancer with transvaginal ultrasonography and colour blood flow imaging.

OBJECTIVE--To assess the value of transvaginal ultrasonography with colour blood flow imaging in detecting early ovarian cancer in women with a family history of the disease. DESIGN--Study of self referred symptomless women with a close relative who had developed the disease. Each woman was screened to detect persistent lesions and defined changes in ovarian volume. Morphological score and pulsatility index were recorded. SETTING--Ovarian screening clinic. SUBJECTS--1601 self referred women. INTERVENTIONS--Women with a positive screening result were recommended to have further investigations. MAIN OUTCOME MEASURES--Findings at surgery and histology of abnormal ovaries. Morphological score > or = 5 and pulsatility index < 1.0 at last scan. RESULTS--Women were aged 17 to 79 (mean 47) years; 959 (60%) were premenopausal, 469 (29%) were naturally postmenopausal, and 173 (11%) had had a hysterectomy. 157 women had a pedigree suggestive of the site specific ovarian cancer syndrome and 288 of multiple site cancers. 61 women had a positive screening result (3.8%, 95% confidence interval 2.9 to 4.9%), six of whom had primary ovarian cancer detected at surgery (five stage Ia, one stage III). Use of a high morphological score or a low pulsatility index increased the odds of finding ovarian cancer from 1:9 to about 2:5 (1:1 in the highest risk groups). Five interval cancers were reported (three ovarian and two peritoneal). Eight of the 11 cancers developed in women with pedigrees suggestive of inherited cancer. CONCLUSIONS--Transvaginal ultrasonography with colour flow imaging can effectively detect early ovarian cancer in women with a family history of the disease. The screening interval should be less than two years.

Outcome of expectant management of spontaneous first trimester miscarriage: observational study

Abstract Objectives: To evaluate the uptake and outcome of expectant management of spontaneous first trimester miscarriage in an early pregnancy assessment unit. Participants: 1096 consecutive patients with a diagnosis of spontaneous first trimester miscarriage. Methods: Each miscarriage was classified as complete, incomplete, missed, or anembryonic on the basis of ultrasonography. Women who needed treatment were given the choice of expectant management or surgical evacuation of retained products of conception under general anaesthesia. Women undergoing expectant management were checked a few days after transvaginal bleeding had stopped, or they were monitored at weekly intervals for four weeks. Main outcome measures: A complete miscarriage (absence of transvaginal bleeding and endometrial thickness <15 mm), the number of women completing their miscarriage within each week of management, and complications (excessive pain or transvaginal bleeding necessitating hospital admission or clinical evidence of infection). Results: Two patients with molar pregnancies were excluded, and 37% of the remainder (408/1094) were classified as having had a complete miscarriage. 70% (478/686) of women with retained products of conception chose expectant management; of these, 27 (6%) were lost to follow up. A successful outcome without surgical intervention was seen in 81% of cases (367/451). The rate of spontaneous completion was 91% (201/221) for those cases classified as incomplete miscarriage, 76% (105/138) for missed miscarriage, and 66% (61/92) for anembryonic pregnancy. 70% of women completed their miscarriage within 14 days of classification (84% for incomplete miscarriage and 52% for missed miscarriage and anembryonic pregnancy). Conclusions: Most women with retained products of conception chose expectant management. Ultrasonography can be used to advise patients on the likelihood that their miscarriage will complete spontaneously within a given time.

Ultrasound screening for familial ovarian cancer

Abstract We have used transvaginal ultrasonography to screen 776 asymptomatic women for familial ovarian cancer. Every woman had at least one first- or second-degree relative develop the disease (677, 87%; and 98, 13%, respectively). The mean age of the study population was 51 years (range, 24 to 78 years); 52% were premenopausal, 36% were naturally postmenopausal, and 12% had undergone a hysterectomy. Overall, 43 women (5.5%) were referred for surgical investigation and 39 had a laparotomy. Nineteen/thirty-nine (48%) had bilateral ovarian masses, and 15% of abnormal ovaries had more than one type of histopathology. Twenty-three tumors and thirty-two tumor-like conditions were detected. There were 3 cases of primary ovarian cancer (prevalence, 3.91000), all FIGO stage Ia. None of the women has developed ovarian cancer within the first year of the scan (giving a provisional detection rate of 100%). The false positive rate was 40773 (5.2%), the predictive value of a positive screen result was 7.7%, and the odds in favor of finding any mass at laparotomy were about 19 to 1 or for any tumor, 1 to 1. At surgery the odds against finding primary ovarian cancer were 12 to 1. The positive predictive value of the screening procedure and the prevalence of the disease were significantly higher than the corresponding values from a previous population-based screening program.

Differential effects of transdermal estradiol and sequential progestogens on impedance to flow within the uterine arteries of postmenopausal women

OBJECTIVE To investigate the relationship between estradiol (E2), progestogen, and impedance to blood flow in the uterine artery. SUBJECTS Twelve postmenopausal women treated for two cycles with transdermal E2, 0.05 mg/d, with either norethindrone acetate, 0.7 mg, or medroxyprogesterone acetate, 10 mg added sequentially. MEASUREMENTS Transvaginal ultrasonography and color flow imaging were used to measure the pulsatility index in the uterine arteries before and during the E2-only and combined E2/progestogen phases. RESULTS The mean pulsatility index fell to 53% of its pretreatment value within 12 days E2 administration (P < or = 0.0001) and was 66% of its pretreatment value in the combined phase (P < 0.005). Similar changes were seen in cycle 2. Time since menopause was correlated with the pretreatment pulsatility index (r = 0.674, P < 0.05) and change in pulsatility index on treatment (r = 0.856, P < 0.001). CONCLUSION Gonadal hormones have a profound effect on arterial tone in postmenopausal women; this action may help explain some of the beneficial effects of estrogen on arterial disease risk.

Detection of endometrial cancer by transvaginal ultrasonography with color flow imaging and blood flow analysis: a preliminary report

A prospective study was undertaken to assess whether changes in uterine blood flow could be used to detect endometrial cancer in 138 selected postmenopausal women (34 had uterine bleeding, 17 with endometrial cancer; 104 did not have uterine bleeding; 1 had endometrial cancer). Thirty-five of the asymptomatic women were receiving estrogen replacement therapy (ERT). The endpoints were endometrial (including tumoral) thickness and a pulsatility index (PI) derived from flow velocity waveforms recorded from both uterine arteries and from within a tumor. We found an overlap in endometrial thickness between those women with endometrial cancer and those without. The mean arterial PI value was invariably lower in women with postmenopausal bleeding and endometrial cancer (mean 0.91, range 0.31-1.49) than in those with other reasons for the blood loss (mean 3.83, range 1.95-6.40). The index was 1.10 in the woman with endometrial cancer but no sign of postmenopausal bleeding. Blood flow impedance was inversely related to stage of cancer. PI values in healthy women tended to increase slightly with age, but decrease during ERT. The detection rate was 100% within the limitations of the study design, and the false-positive rate was 1% for all women not receiving ERT and 11% for patients receiving ERT. Malignant tumors show signs of altered vascularization and a low PI (mean 0.49, range 0.29-0.92). We conclude that transvaginal ultrasonography, with or without color flow imaging, and blood flow analysis can be used to detect endometrial cancer in women with postmenopausal bleeding. A screening procedure for asymptomatic women must allow for changes in uterine blood flow during ERT.

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.

Ultrasound studies of vascular and morphological changes in the human corpus luteum during the menstrual cycle

OBJECTIVE To determine changes in corpus luteum (CL) volume, echogenicity, vascularity, and P production relative to a positive test result for urinary LH and day 1 of next menses. SUBJECTS Thirteen healthy volunteers (age 23 to 32 years). INTERVENTIONS All women underwent transvaginal ultrasonography on cycle day 11 and a urinary LH self-test was used daily. The plan was to rescan all women immediately after a positive test result and then at least every 48 hours (until day 6 of the next cycle); samples of peripheral blood were taken for analysis. MAIN OUTCOME MEASURES The times of follicular rupture, a positive urinary LH test, and the start of menses; CL volume and echogenicity, maximum peak systolic velocity and minimum impedance, the circulating levels of serum P, E2, LH, and FSH. RESULTS Nine women fulfilled criteria for an ovulatory cycle. There was a good correlation between peak systolic velocity, CL volume, and the concentration of serum P from day 4 to 10 after a positive LH test. Peak systolic velocity reached a maximum value between days 7 and 9 relative to a positive urinary LH test and started to decline from day 1 of menses minus 3, 4 days. CONCLUSION Changes in peak systolic velocity from the time of a positive urinary LH self-test might be a useful adjunct for monitoring CL function.

Detection of endometrial cancer in postmenopausal women by transvaginal ultrasonography and colour flow imaging.

About 3700 new cases of endometrial cancer are reported in the United Kingdom each year. The incidence of the disease increases considerably during the fifth decade of life and reaches a peak between the ages of 60 and 65. Uterine bleeding is the most common initial symptom after the menopause and necessitates invasive investigation (for example, dilatation and curettage). About a tenth of women with postmenopausal bleeding have endometrial cancer. A less invasive technique with a high rate of detection of the disease and a low rate of false positive diagnoses would be of value for selecting those women who require diagnostic surgery. Pelvic ultrasonography yields detailed images of the uterus. Although a thick endometrium may be a sign of pathological processes, no morphological features that are unique to malignant disease have been identified.1 Recently the use of transvaginal pulsed Doppler probes, with and without colour flow imaging, has shown that uterine blood flow changes during the menstrual cycle.2 Furthermore, trans vaginal ultra? sonography with colour flow imaging has shown that the presence of intratumoral vascularisation with a low impedance to blood flow can be used as an end point in screening programmes for early ovarian cancer.34 We report the use of these techniques to measure the impedance to uterine arterial and intra? tumoral blood flow and hence detect endometrial cancer in women with postmenopausal bleeding.