1 Gynaecology Research Group, Department of Obstetrics and Gynaecology, and 2 Epidemiology, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, and Department of Obstetrics and Gynaecology, 3 King's College Hospital, London and 4 Queen's University, Belfast, UK
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Abstract |
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Key words: bleeding/endometrium/HRT/menopause/trimegestone
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Introduction |
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Progestogens can also cause premenstrual tension (PMT) symptoms, such as irritability, bloatedness, fluid retention and cyclical mastalgia. These PMT symptoms appear dose-related (Magos et al., 1986). However, optimizing the progestogen dose to below minimum effective dose may jeopardize endometrial protection and may also cause poor cycle control. Because the duration of progestogen administration appears to be an important factor in protecting the endometrium (Sturdee et al., 1978
; Whitehead, 1978
), shortening the exposure to the progestogen may increase the risk of hyperplasia and cancer.
Trimegestone is a novel norpregnane progestogen which in binding studies with human recombinant steroid receptor has been shown to have potent progesterone and a very low androgen receptor affinity, and no detectable affinity for the oestrogen receptor (Bouchoux et al., 1995). Such a profile makes this progestogen suitable for evaluation in combination with oestradiol in HRT. We now report a dose-ranging study of four doses of trimegestone added sequentially to oral oestradiol. Data were collected on the patterns of vaginal bleeding, the endometrial histology, and the control of menopausal symptoms in women receiving treatment over 6 months.
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Materials and methods |
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We recruited apparently healthy women, aged 4565 years, and with an intact uterus who were at least 6 months postmenopausal. All had either taken HRT for more than 2 years, had had HRT for at least 1 year with pretreatment follicle-stimulating hormone (FSH) and oestradiol concentrations within the postmenopausal range, or had been amenorrhoeic for at least 6 months with FSH and oestradiol concentrations within the menopausal range. Patients who had previous use of an oestradiol implant were excluded from the study. Tests of liver and renal function were performed and those women with abnormalities were excluded. All women aged over 50 years had to have undergone mammography within 3 years before entry, and all women were required have had a normal cervical smear within 6 months before entry. At baseline, general, breast and pelvic examinations were required to be normal. An endometrial biopsy was obtained using the Vabra curette at the screening visit and fixed in formol saline. Patients were excluded if the histology showed any evidence of hyperplasia or cancer.
During the study, additional sex steroid treatments were not allowed and women who used treatments known to interfere with steroid metabolism were withdrawn. At the final visit, general, breast and pelvic examinations were repeated and a further endometrial biopsy was obtained using the Vabra curette on day 23 or 24 of the last treatment cycle and again fixed in formol saline. If the biopsy material at this visit was inadequate for histological assessment, then hysteroscopy under local anaesthesia was performed to confirm that the endometrial surface appeared normal and atrophic. All endometrial biopsies were evaluated by two independent pathologists (Dr J.Pryse-Davies and Dr C.Bergeron) who were blinded to the trimegestone dose.
Treatment
Allocation to treatment which lasted for six 28-day cycles was random. Each cycle consisted of oral micronized oestradiol (RU 3499: Hoechst Marion Roussel, Romainville, France) 2 mg/day for 28 days together with trimegestone tablets (Hoechst Marion Roussel) (either 0.05, 0.1, 0.25 or 0.5 mg per day) for days 1528 of each cycle. The first visit was a pre-study assessment and took place 23 weeks before commencement of the 168-day treatment. All participants were assessed clinically at the end of the third cycle and then on the 23rd or 24th day of the sixth treatment cycle. Failure to attend on that day meant that a seventh cycle of treatment was prescribed.
Assessment of symptom control
Women completed the Greene Climacteric Scale (Greene, 1976) and answered questions about breast tenderness, bloating, nausea, abdominal cramps, irritability, leg cramps, acne, seborrhoea and headaches. The scales were completed at baseline and the end of the third and sixth treatment cycles.
Daily diaries
`Bleeding' was defined as vaginal blood loss requiring a sanitary pad or tampon: `spotting' was defined as that which did not require sanitary protection. We defined the first day of the oestrogen phase as a fixed reference time, `day 1'. Diaries were kept for each treatment cycle; bleeding was scored as 0 = no bleeding, 1 = spotting, 2 = slight bleeding, 3 = moderate bleeding and 4 = heavy bleeding. The total bleeding score was the sum of the daily scores.
Definitions
The following definitions were applied: a `bleeding episode' was defined as bleeding for one or more days with at least two bleed-free days before and after; progestogen-associated bleeding was vaginal bleeding with any day of that episode starting between day 22 of one cycle and day 7 of the next cycle, inclusive (all other bleeding was defined as intermenstrual bleeding); the `bleeding interval' was the number of days between the first day of bleeding of two consecutive progestogen-associated bleeding episodes.
At the end of the third and sixth treatment cycles, the diaries were collected and checked for accuracy and completeness. They also served as an additional check of compliance because a box had to be ticked when every tablet was taken. Used medication packs were collected and all remaining tablets were counted. If <80% of the medications had been used, then the patient's data were excluded from the analyses. All adverse events and concomitant medications were also recorded. Those cycles in which data were incomplete (incomplete diaries) were excluded from the bleeding analysis. Bleeding data from the cycles in which the endometrial biopsy was performed were also excluded.
Statistical analysis
Data were collected from up to seven cycles for each woman and these repeated measures were analysed using mixed models. For continuous data, the residual maximum likelihood (REML) was used (Patterson and Thompson, 1971) to fit the model. For binary data, a generalized linear mixed model with binomial errors was used (Brestlow and Clayton, 1993
). Calculations were made using GENSTAT (GENSTAT 5 Committee, 1993
). Patient data that were not collected separately for each cycle were analysed using analysis of variance (ANOVA) or the chi-square test. The transition probabilities in Table V
were calculated by the method of Harlow and Zeger (1991).
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Results |
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The number of women starting and continuing treatment at each dose is shown in Table I; there was no statistically significant difference between the four dose groups. Table II
lists the number of women reporting adverse events and severe adverse events, and the number in whom study medication was discontinued. It is possible for the same patient to appear in all three categories, e.g. in the 0.05 mg/day group, 36 women reported breast pain as an adverse event; six described it as severe and five withdrew as a result. There were no statistically significant differences between the numbers of patients from each trimegestone dose group for adverse events, severe adverse events or discontinuation of medication. The following adverse events occurred and led to the discontinuation of study medications. Two cases of thrombophlebitis were reported, one in each of the 0.05 mg and 0.5 mg trimegestone groups. One case each of raised blood pressure, allergic reaction and weight loss was reported in the 0.05, 0.1, 0.25 and 0.5 mg dose groups. Irritability and depression were contributory factors in the withdrawal of seven women, headache in eight and gastrointestinal symptoms in 12, though none of these adverse events was related specifically to the trimegestone phase of treatment. One case of breast carcinoma was diagnosed during the study and thus the woman was withdrawn; a subsequent review revealed that the cancer had been present but not identified in the pretreatment mammogram.
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Effects on climacteric symptoms
There was a significant improvement in the anxiety, depression, somatic, vasomotor and sexual components of the Greene Climacteric Scale in all treatment groups (ANOVA, P < 0.01) after 3 months of treatment, which was maintained at the end of the study. There was no statistically significant difference in the improvement of scale components between those women who did not have HRT before starting the study and those who did; neither was there any statistically significant difference between the treatment groups (data not shown).
Frequency of progestogen-associated- and intermenstrual bleeding and amenorrhoeapa
These data are presented in Table IIIa (women) and IIIb (cycles). Data are also included in these tables on the number of cycles and women with missing data due to an incomplete diary. It should be noted that data for all women in the last treatment cycle were excluded because of the on-treatment biopsy. There were no significant differences between the four doses for any of these variables.
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The bleeding pattern in individual women
The mean (range) day of onset of bleeding in relation to the trimegestone dose for each woman is shown in Figure 1. The mean day of onset of progestogen-associated bleeding occurred progressively later with higher doses (P = 0.0001). These data suggest that the variability in the day of onset of bleeding is reduced, with a mean day of bleeding onset of day 29 or later. This was more noticeable with the highest dose of trimegestone as more women in this dose group bled on or after day 29. The within-subject variance of the day of onset of progestogen-associated bleeding for women whose day of onset was <29 days was significantly greater than that of women whose mean day of onset was
29 days (P <0.0001).
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Prediction of the day of onset of progestogen-associated bleeding
An investigation was made to determine whether knowing the day of onset of progestogen-associated bleeding in any cycle might predict the day of onset of bleeding in the next cycle (Table V). For example, a day of onset of
28 days in the current cycle was associated with a 74% chance of this day of onset of progestogen-associated bleeding occurring in the next cycle. Absence of such bleeding in the current cycle was associated with a 15% chance of no progestogen-associated bleeding in the next cycle.
Number of days of progestogen-associated- and intermenstrual bleeding per cycle
The duration of progestogen-associated bleeding (in cycles with such bleeding and excluding those cycles without) was 7.7, 7.2, 5.8 and 4.9 days with trimegestone dose levels of 0.05, 0.1, 0.25 and 0.5 mg, respectively. These differences were statistically highly significant (P <0.0001). Comparable data for the number of days of intermenstrual bleeding (in cycles with such bleeding and excluding those cycles without) were 3.4, 2.7, 1.5 and 3.4, respectively.
Total bleeding score
The severity of vaginal bleeding, expressed as a total bleeding score, progressively declined both with the increase in trimegestone dose (P < 0.0001) and over time (P < 0.0001) (Table VI).
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Discussion |
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The endometrial safety data were reassuring, with only one biopsy showing simple hyperplasia. This is below the incidence seen in an untreated population of postmenopausal women. The 98% procurement rate of adequate endometrial biopsies for histological analysis compared favourably with the published data on Vabra curettage (Grimes, 1982) and the sampling rate in large multicentre studies (Sturdee et al., 1994
). There were only four patients from whom an endometrial biopsy could not be obtained, and in all four the uterine cavity was shown by hysteroscopy to be atrophic. There were no statistically significant differences between the histological results from the four dose groups. The finding of atrophic and/or inactive endometrium in a woman experiencing regular withdrawal bleeding is intriguing, and either reflects regional differences within the endometrium or suggests a different mechanism for bleeding as compared with that seen in women with spontaneous postmenopausal bleeding in the absence of a specific pathology.
There was no clear dose response with respect to secretory changes in endometrial histology (Table VII). Therefore, one interpretation of the data would be to recommend the 0.05 mg/day dose of trimegestone because this is the lowest effective dose in the present study which provided endometrial safety. However, data on the patterns of bleeding might lead to a different conclusion.
As the trimegestone dose increased, the mean day of onset of progestogen-associated bleeding occurred later (Table IVb), and the variability in the onset of such bleeding was also reduced (Figure 1
). This pattern, with `early' bleeders having a greater variability in the length of bleeding interval compared with `late' bleeders, confirms our previous report of 103 women using oral oestradiol and norethisterone (Habiba et al., 1996
). The current study also shows that both the duration and severity of progestogen-associated bleeding (Table VI
) are reduced as the trimegestone dose was increased. The severity of bleeding was also reduced over time.
This interesting association of a later onset and shorter duration of bleeding suggests that a fuller differentiation of the endometrium before shedding occurs with higher progestogen doses. `Early-onset' bleeding and the association with a longer duration of blood loss may reflect regional differences within the uterus in maturation and shedding of the endometrium with a lower dose of progestogen.
The chance of transition from a particular day of onset of bleeding into another pattern was calculated. Women who bleed while still in the progestogen phase had a higher incidence of early bleeding in the next cycle; conversely `later-onset' bleeding in one treatment cycle was more likely to be associated with late-onset bleeding in the next cycle (Table V). The finding of a later onset of bleeding in the treatment cycle being associated with a more predictable pattern of bleeding is in accordance with our previous report (Habiba et al., 1996
), and suggests that this method of predicting the day of onset of bleeding might be used both by the clinician and patient to anticipate the pattern of bleeding when using a particular preparation of HRT.
The increased number of episodes of intermenstrual bleeding, which appeared to be of shorter duration as the dose of trimegestone increased, may be due to the progressive delay in the onset of bleeding with higher doses, which may include an extension of the bleeding outside the progestogen-associated bleeding window. There is a tendency for more bleeding days in the intermenstrual bleeding window in the 0.5 mg dose group, which may be due to the progressively later onset of bleeding. However, the frequency of intermenstrual bleeding was too low to permit further interpretation of this increase.
Although 12 women experienced adverse events related to withdrawal bleeding for which they discontinued the medication, the effect of the trimegestone dose was so dominant that their exclusion had no significant impact on the data.
In summary, we have shown that the dose of trimegestone is the major determinant of the pattern of uterine bleeding. Higher doses were associated with a later onset of bleeding, a shorter duration, and less heavy bleeding. Variability in the duration of bleeding also decreased. We believe that all of these factors will improve patient continuance and therefore consider that for routine addition to oral micronized oestradiol in postmenopausal women, the highest dose of trimegestone (0.5 mg) is to be preferred over the lowest (0.05 mg).
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Acknowledgments |
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Notes |
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References |
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Submitted on August 12, 1998; accepted on November 23, 1998.