Postmenopausal Tibolone Therapy: Biologic Principles and Applied Clinical Practice

Morris Notelovitz, MD, PhD, MB, BCh, FACOG, FRCOG

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The Endometrium and Endometrial Cancer

The postmenopausal endometrium is atrophic. Endometrial proliferation has, however, been found in 2%-16% of untreated postmenopausal women in whom endometrial biopsies were performed.[45]

Clinical message: the synthesis of estrogen continues postmenopausally in all women but to varying degrees in estrogen-sensitive tissues such as the breast and endometrium. Exogenous HT provides an added stimulus: endometrial proliferation has been observed in 8%-14% of women receiving CCHT[46]; approximately 7% of women were found to have endometrial proliferation after 1 or 2 years of treatment with tibolone. This is not dose dependent. The shift from atrophic to proliferative endometrium following tibolone therapy is balanced by the conversion of proliferative to atrophic histology.[47]

Endometrial cancer is a disease of aging: 75% of untreated women with endometrial cancer are postmenopausal. Endometrial cancer follows a well-defined and predictable histologic progression: simple hyperplasia to complex hyperplasia with and without atypia and then to carcinoma in situ and invasive cancer. Women with complex hyperplasia and atypical features have a 23% risk of endometrial cancer over the next decade.[48] Lesser degrees of histologic abnormality have a very low risk of developing into endometrial cancer.

The database of observational studies reporting the prevalence of endometrial cancer and tibolone therapy needs to be carefully scrutinized to exclude the clinical practice bias of prescribing tibolone to women who have either not been responsive to HT, or who have relative contraindications for HT. In one case control study (GPRD), the relative risk of developing endometrial cancer for "ever use" of tibolone (which included prior use of HT) was 1.54 vs no increase (RR 1.19) in women who had only used tibolone.[49] Data from another UK study reported significantly more uterine bleeding-related diagnostic procedures after tibolone than after sequential HT prescriptions, suggesting the preferential use of tibolone in women with a history of dysfunctional uterine bleeding.[50]

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