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New Progestin –How Strong Is the Evidence?
The benefits of oestrogen replacement therapy is widely established, yet the continuation rates with these health promoting therapeutics remain low throughout the western world.
In addition, women with intact uterus require the addition of a progestogen to protect the endometrium against endometrial hyperplasia and carcinoma. When a progestogen is added sequentially uterine bleeding is re-initiated. In postmenopausal women this unwelcome event may be tolerated if the bleeding is regular and not heavy.
However, more than 50% of women stop HRT due to unacceptable bleeding pattern. Indeed 50% of women on HRT experience withdrawal bleeding that is poorly predictable and heavy. Sequentially administered progestogen in current standard doses used in HRT preparations cause pre-menstrual tension type of symptoms, such as irritability, bloatedness, fluid retention and mastalgia in about 30% of users. By reducing the dose of the progestogen to reduce the frequency of these adverse effects, the regularity of the cycle may be jeopardised. It is possible to modulate an unacceptable bleeding pattern by increasing the dose of the progestogen, but this dose increase, heightens the frequency of progestogen associated adverse effects. There is a clear need within the list of therapeutics available to date for a new progestin which is effective in protecting the endometrium against the proliferative influence of oestrogen and at the same time, minimally affects systemic metabolism and does not induce PMT type of symptoms.
Trimegestone is a novel norpregnane progestin, which in human recombinant receptor binding studies demonstrate potent progesterone receptor, very low androgen receptor affinities, and no detectable affinity to oestrogen receptor. Trimegestone is being developed for use in conjunction with oestrogen for postmenopausal HRT.
In order to optimise the dose of trimegestone required for endometrial safety, a dose ranging study was conducted. Oral trimegestone was administered at 0.05, 0.1, 0.25, and 0.5mg per day, days 15 - 28 along with oral micronised E2, 2mg daily. The majority of women in the 4 dose groups experienced relief of climacteric symptoms by the end of the third treatment cycle. The incidence of PMT like symptoms was low and did not differ between the 4 dose groups. After 6 months of treatment, the bleeding pattern showed a clear dose dependant modulation such that the higher the dose of trimegestone administered the more predictable was the day of onset of bleeding, and the shorter and lighter the bleeding episodes became.
Furthermore, in an extension of the above study for a further 6 months using a single dose of trimegestone 0.25mg/day, days 15 - 28, a fine modulation of the bleeding pattern was further documented. Women who were treated with the lower doses of trimegestone experienced an improvement in the regularity of the day of onset of bleeding, shorter and scantier bleeding episodes while women in the 0.5mg trimegestone dose group experienced more variable day of onset, longer and heavier bleeding than during their first 6 months. Women who continued with the 0.25mg trimgestone experienced no change in the bleeding pattern. These data suggest a dominant effect of the dose of trimegestone and that longer continuation with this sequential HRT regimen does not influence the bleeding pattern.
In 96% of endometrial specimens obtained at the end of the study, secretory changes were documented. Therefore, it is logical to recommend the use of the lowest dose of this progestogen given the histological features of the endometrium; but our recommendation is the use of the 0.5mg per day in view of the excellent bleeding profile this higher dose of trimegestone has induced.
Endometrial histology assessed in the orthodox manner did not give us a clue to explain the 4 different types of bleeding episodes encountered in women treated with the 4 doses of trimegestone. We adopted an histo-morphometric analysis and examined 13 features of endometrial tissue components reported to be cycle modulated. Our samples included control endometria of the natural cycle and the endometrial samples collected at the end of the 6 months dose ranging study. To highlight the differences between the groups a linear discriminant analysis was performed. The linear discriminant functions produce weighted combinations of the 13 measurements which best separate the nine groups (4 doses of trimegestone, and 5 phases of the natural cycle). The results of this analysis show no dose dependent difference in endometrial morphology, and have identified parameters which discriminate the trimegestone treated endometrium from those of individual phases of the natural cycle. Immunohistochemical studies of endometrial leucocytes and their proliferation markers showed a pattern of infiltration close to that of the late luteal phase of the natural cycle, whereas norethisterone treated endometrium is marked by a six fold increase in leucocytes population. The lipoprotein profile measured at baseline, 3 and 6 month during the dose ranging study confirmed the fact that trimegestone, irrespective of the dose, did not negate the beneficial effects of oestrogen on lipids.
However, in another double blind study comparing E2+ sequential trimegestone in two doses (0.25 and 0.5 mg/ day for 14 days) to E2+ sequential NET 1mg/day for 10 days, every 28 days, for 12 months showed more beneficial effects on HDL-cholesterol, ApoA1 in the two trimegestone dose groups compared to NET based HRT. In this study symptoms control was similar in the 3 treatment groups but the bleeding pattern was best demonstrated in the E2 + 0.5 mg trimegestone regimen.
In conclusion these studies have demonstrated an effective and well tolerated new progestin which may add an important therapeutic choice for post-menopausal women to enhance long term acceptance of HRT.