Trimegestone and the endometrium

The health benefits of long term postmenopausal HRT are well recognised, but the re-initiation of cyclical bleeding, especially when irregular or heavy, has a profound impact on continuation rates. In this thesis, this clinical problem was investigated in 256 postmenopausal women who participated in a randomised dose ranging study of sequentially administered trimegestone (4 doses) with continuous micronised oestradiol, for 6 months.;A strong dose dependent modulation of the bleeding pattern was documented. Women in the higher trimegestone dose groups had better bleeding patterns compared to those on the lower doses. This was subsequently confirmed when 134 women completed a further 6 months' extraction study with a single dose of trimegestone (0.25 mg). The presence of submucous fibroids in 176 women predicted the occurrence of abnormal bleeding pattern, however, the dose of trimegestone remained the dominant factor.;These clinical data led to detailed histological and immunohistochemical evaluation of the endometrial samples collected on day 24 of the last treatment cycle.;The majority of the results showed remarkable similarities between the test endometria and the natural cycle. None of the parameters clearly demonstrated a dose-dependent effect of trimegestone. When the expression of metalloproteinases -1 and -3 were assessed in specimens from women who received the highest and the lowest dose of trimegestone, where the bleeding pattern was completely different, no dose effect was demonstrated.;These conclusions led me to question the ability to demonstrate this apparent similarity of endometrial effect between trimegestone and progesterone. For this I have developed a primary stromal cell culture system, and examined the expression of MMP-1, and -3 mRNA in these cells. Similarity between trimegestone and progesterone was again demonstrated.