Recommendation for the collection and analysis of endometrial biopsies for hormone therapies.

The assessment of endometrial safety is one of the key requirements for the clinical development of new products for hormone therapy (HT) to treat menopausal symptoms in women who have a uterus. Both the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) provide detailed guidance on the requirements for the evaluation of biopsies to prove endometrial safety. However, there are some discrepancies between the European and the US requirements, making it difficult to fulfil both guidelines simultaneously. In order to facilitate multinational clinical trials performed within clinical programs to develop novel HT products, we developed an approach considering both guidance documents as far as possible and proposed solutions for issues that are inconsistently described in these guidelines. A table with the required sample sizes is given. Our recommendation for a unified approach for the estimation of the hyperplasia rate for hormone therapies fulfils the intent of the recommendations of both the FDA and the EMA and thus leads to a globally harmonized drug development for hormone therapies.

Benign and hyperplastic endometrial changes associated with tamoxifen use.

For nearly 20 years, tamoxifen has been successfully used in the management of breast cancer. Tamoxifen is a mixed estrogen agonist/antagonist that has a proliferative effect on the endometrium. The drug has been associated with a higher percentage of endometrial polyps and hyperplasia than in control patients as well as slightly increased risk of endometrial cancer. Although patients need to undergo annual gynecologic exams and abnormal vaginal bleeding needs to be aggressively followed up, the utility of routine gynecologic screening of tamoxifen patients has not been established and requires further study. Transvaginal sonography is a useful tool for detecting endometrial proliferation; however, an appropriate cut-off point for further intervention must be established. A cut-off point that is too low for abnormal endometrial thickness would result in a large number of unnecessary endometrial biopsies. Routine office endometrial biopsy needs further study as a screening method for breast cancer patients on tamoxifen.

Endometrial hyperplasia and neoplasia. Cytologic screening with the Endopap endometrial sampler.

A new endometrial sampling device, the Endopap, was tested in a series of 851 patients. This sampler is of simple design, without moving parts, inexpensive and easy to use. Cellular samples proved adequate in 90% of the cases, usually with very abundant material. Endometrial cancer shed atypical cells in all 20 cases studied. However, only about half the patients with adenomatous hyperplasia were correctly identified by the endometrial sample. This fact seems to reflect the lack of adequate morphologic criteria for the recognition of endometrial hyperplasia; this situation prevails with all types of endometrial cell samplers.