W. P. Collins

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.

Ovarian size in postmenopausal women

Summary. Ovarian volumes have been determined by pelvic ultrasonography in 2246 apparently healthy postmenopausal women of whom 2221 were included in the statistical analysis. Factors associated with gonadal size have been identified, and reference ranges for derived indices have been determined for use (in association with criteria for abnormal morphology) in a screening programme for ovarian carcinoma. The right ovary was present in 98·9% of subjects and the left in 99 · 1 %. The mean (SD; range) of right and left ovarian volumes were 3·58 (1·40; 1·00–14.01) and 3·57 (1·37; 0·88–10·9) ml respectively. Significant predictors of ovarian volume were years since the menopause, weight, parity, age at menopause, a history of hormone replacement therapy, and previously diagnosed breast cancer. Abnormal ovarian volumes were assessed from a score equal to the (observed mean log volume (MLV) minus the predicted MLV)/0·327. A simplified nomogram has been prepared for routine clinical use. The relative abnormality of one ovary was assessed from a ratio score equal to loge (larger ovarian volume/smaller ovarian volume)/0·211 compared with the 99th centile for the Gaussian distribution.

HYSTERECTOMY, HORMONES, AND BEHAVIOUR: A Prospective Study

60 premenopausal women were assessed before and after hysterectomy for menorrhagia or fibroids or both. Their mood, sexual functioning, and plasma oestrogens and gonadotrophins were regularly assessed for a period of up to 3 years. Patients were randomly assigned to receive either oestrone sulphate or placebo tablets during the trial. No evidence was found that this group of patients showed depression or sexual difficulties related to the hysterectomy. In comparison with their baseline gynaecological condition, they showed improved mood and vigour and unimpaired sexual activity.

Novel screening strategies for early ovarian cancer by transabdominal ultrasonography

Summary. Data collected during a prospective study to assess the efficacy of detecting early ovarian cancer by transabdominal ultrasonography have been used to refine and extend the screening procedure. The analysis was based on results from 5479 self‐referred asymptomatic women, who were scheduled to undergo three annual screens consisting of one or more ultrasound scans. A positive result (based mainly on the presence of abnormal morphology) was obtained at 338 screens (326 women). Five patients with primary ovarian cancer (four stage la, one stage 1b; two at screen 1, three at screen 2) were identified (prevalence 0.09%). The apparent detection rate was 100% and the false‐positive rate (FPR) was 3.5% at screen 1 and 2.3% overall. The use of abnormal morphology, or the maximum ovarian volume (MOV) >96th centile as alternative criteria for a positive screen result, together with a defined volume change at rescan (VC) would give a FPR of 3.1% at screen 1 and 2.0% overall. The use of abnormal morphology alone at scan 1 and VC at rescan would give an overall FPR of 1.6%. The odds that a positive screen result would indicate the presence of an ovarian mass, a benign tumour, any ovarian cancer or primary ovarian cancer would be about 4 to 1, 2 to 1, 1 to 26, and 1 to 50 respectively. The results provide a more rational basis for the application and development of screening procedures for early ovarian cancer in both pre and postmenopausal women.

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

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.

Monitoring gonadotrophin therapy by real-time ultrasonic scanning of ovarian follicles.

Summary. Real‐time ultrasound scanning of ovarian follicles was performed during 61 cycles in 22 infertile patients being treated with sequential injections of human menopausal gonadotrophin (hMG) and human chorionic gonadotrophin (hCG). Total 24‐h urinary oestrogens were estimated (and in 13 cycles plasma oestradiol) but the amount of gonadotrophin given was based mainly on the ultrasound findings. A retrospective analysis of the results showed that there was a poor statistical correlation between the diameter of the largest follicle and the total urinary oestrogens (r= 0.39) and with the level of plasma oestradiol (r= 0.56), although similar clinical information was obtained by all methods. Ovulation was induced in 58 cycles when the leading follicle had a mean diameter of 20–25 mm (mean 21.3 mm); follicular rupture was observed in 57 cycles and in these cases there was biochemical evidence of luteinization (plasma progesterone >15 nmol/1; total urinary pregnanediol >8 μmol/24h). Three patients (three cycles) were not given hCG; one developed micropolycystic ovaries and two showed evidence of hyperstimulation (one follicle >25 mm diameter, three or more follicles 20–25 mm diameter). Twelve patients became pregnant, all with single fetuses. Subsequently one aborted, one had an ectopic pregnancy, three gave birth to normal babies at term and seven pregnancies are continuing. Real‐time ultrasound scanning of ovarian follicles is a simple, practical method for monitoring follicular growth during the administration of hMG and predicting the response to hCG.

Characteristics of persistent ovarian masses in asymptomatic women

Persistent ovarian masses have been found in a substantial proportion of 5479 self‐selected asymptomatic women who were screened for early ovarian neoplasia. Each woman was scheduled to undergo three ultrasound screens (consisting of 1–12 scans) to detect regressing and non‐regressing masses. A total of 14,594 screens (15,977 scans) was performed. The average interval between successive screens was 595 days (range 214–1134 days). Overall, 650screens (4.4%; 10.1% of women) produced a positive result which became negative with successive scans (four times more frequently in pre‐than naturally postmenopausal women), and 338 screens (2.3%; 5.9% of women) had a final positive result (at least one ovary that was grossly abnormal or contained a persistent mass). Biopsies were taken from 336 ovaries (89% of total, 271 women). Overall, 134 tumour‐like conditions and 119 benign tumours were identified. The detection rate of tumour‐like conditions was 1.5 times higher in premenopausal than naturally postmenopausal women, whereas the proportion of tumours to normal ovaries was similar in both groups. Overall, 51% of tumour‐like conditions and 70% of all tumours were detected at screen 1. Four women had metastatic ovarian cancer (three at screen 1, one at screen 2; two were bilateral). Five women (0.1%) had a primary malignant tumour (two at screen 1, three at screen 2; four were stage la and one was stage Ib). All women are being monitored to obtain additional information about the significance of the findings.

Use of family history in a screening clinic for familial ovarian cancer

We have estimated the risks of ovarian and other types of cancer in first-degree relatives of women who have developed the disease (the index patients). The number of deaths from each type of cancer was determined from pedigrees taken from 391 self-referred, asymptomatic women attending a screening clinic for familial ovarian cancer. These values were compared with the expected number of deaths for women in the general population (calculated from life tables), and the relative risks were used to estimate lifetime risks. The overall relative risk were 4.5, 1.4, 1.3, and 1.1 for ovarian, stomach, breast, and endometrial cancers, respectively. The risks were invariably higher if the index patient was < 55 years old. Ovarian cancer appeared to have no clear inheritance pattern in 290 pedigrees and there was no increased risk for the first-degree relatives. Eighty-two pedigrees were compatible with a diagnosis of a multiple-site cancer family syndrome and the relative risks were 6.1, 2.8, 3.7, and 2.7 for ovarian, breast, stomach, and colorectal cancer, respectively. There was evidence of site-specific ovarian cancer in 19 families; the relative risk for the first-degree relatives was 39.1 and the lifetime risk 1 in 2. We believe that family history can be used to identify women who are at a high risk of developing ovarian and certain other types of cancer. This information can be used to counsel women attending ovarian cancer screening clinics and to maximize the usefulness of current resources.

Effects of subcutaneous oestradiol implants on ovarian activity

Summary. The effects of subcutaneous oestradiol implants on ovarian activity were investigated in 14 ovulating premenopausal women. Treatment with either 100 mg or 150 mg oestradiol was combined with cyclical oral norethisterone from days 20 to 26 of the cycle to ensure regular withdrawal periods and prevent endometrial hyperplasia. Ovarian function was monitored by regular pelvic ultrasonography and urinalysis over a period of nine cycles. During the first three cycles after hormone implantation, follicular development continued in almost half the study group, but only one of the women in each treatment group showed signs of follicular rupture and luteinization. By the sixth cycle, over half the women given the lower dose of oestradiol were developing follicles, including a large functional cyst in one, but none of them ovulated. A further implant given early in the seventh cycle was associated with ovarian suppression in all cases. Both doses of implant elevated the excretion of oestrone‐3‐glucuronide compared to pretreatment. The contraceptive and therapeutic implications of these results are discussed.

SCREENING FOR EARLY OVARIAN CANCER

Transvaginal ultrasound scanning with colour Doppler imaging can be used to detect early ovarian cancer. About one in three women with a family history of the disease and a positive screening result (i.e. a persistent intraovarian mass with a characteristic blood supply) will have histological signs of primary cancer. A randomized controlled clinical trial should be undertaken to assess whether screening and immediate treatment of women from the general population will improve survival rates from the disease.