1 Department of Obstetrics and Gynaecology, and 2 Department of Cellular Pathology, John Radcliffe Hospital, Headington, Oxford, UK
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Abstract |
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Key words: endometrium/pre-treatment/resection
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Introduction |
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The rate of amenorrhoea after TCRE and patient satisfaction is increased in those who have been treated pre-operatively with pharmacological agents to thin the endometrium (Romer and Schwesinger, 1997; Seeras and Gilliland, 1997
). This has been attributed to the decreased endometrial thickness, uterine size, fluid absorption and operating time together with better operative conditions associated with endometrial preparation prior to TCRE (Vercellini et al., 1994
, 1996
; Donnez et al., 1997
; Sorrensen et al., 1997
). In addition, TCRE may be technically difficult if the endometrium is thick, as in the late secretory phase of the menstrual cycle. Although many of these problems may be avoided by performing the procedure in the proliferative phase of the menstrual cycle, it is not always possible to schedule the procedure at the appropriate time.
Endometrial pre-thinning is useful in enabling the resection of a sufficient depth of endometrium and myometrium. This is important as endometrial stroma and glands may be deeply situated and capable of continued growth if not completely removed. It has been claimed that resection or ablative techniques should include up to 3 mm of myometrium (Reid et al., 1992). In support of this is the finding of endometrium in hysterectomy specimens of women who have undergone unsuccessful endometrial resections (McCulloch et al., 1995
).
Despite the theoretical advantages of pre-treating the endometrium, some authors have questioned its need and have described no improvement in clinical outcome from pre-treatment (Magos et al., 1991). Many comparisons have been made of the clinical outcome of patients pre-treated with various medical agents, but few studies have related the histological findings resulting from various endometrial pre-treatments and control groups to clinical outcome (Sutton and Ewen, 1994
; Garry et al., 1996
).
The primary aim of this study was to perform a prospective randomized trial comparing three endometrial pre-treatment agents with no pre-treatment prior to TCRE with respect to amenorrhoea rates 1 year after surgery. Secondary aims were to compare the histological findings at the time of operation and patient satisfaction 1 year after surgery.
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Materials and methods |
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In all, 100 consecutive women booked for a TCRE for surgical management of excessive uterine bleeding, based on history, were randomized to one of the four pre-treatment regimes commencing on the fifth day of the menstrual cycle for 8 weeks before admission. Patients taking any hormonal medication or with a uterine size clinically greater than the equivalent of a 10 week pregnancy were excluded from the study. Randomization was performed at the time of scheduling the procedure by an independent member of staff not involved in the study using numbered sealed opaque envelopes. A total of 100 envelopes containing pre-allocations to the four pre-treatment regimes in equal groups of 25 were used. The pre-treatment regimes were: (i) danazol 200 mg every 8 h; (ii) MPA 10 mg every 8 h until 1 week prior to operation at which time the treatment was stopped to induce a withdrawal bleed; (iii) nafarelin nasal spray, 200 µg every 12 h and (iv) no pre-treatment. Women randomized to no pre-treatment had their operation performed immediately after menstruation ceased. Patients (n = 25) were randomized to each pre-treatment group. Ethical approval for the study was obtained and all women gave informed consent.
To eliminate any bias in results from operators of differing experience, all endometrial resections were performed by the same surgeon (M.D.G.G.) who was blinded to the treatment allocation. Surgery was performed using a continuous flow resectoscope with glycine irrigation. In each case, rollerball diathermy was used initially to the cornual areas and to the myometrial surface on conclusion. Details of operative findings and any complications or difficulties encountered were recorded. Two representative strips of resected endomyometrium were obtained from each patient for histological examination. Staging of the endometrium together with endometrial and myometrial thickness was assessed by a single histopathologist (W.G.) who was also blinded to the treatment allocation.
The primary outcome measures were: (i) thickness of the endometrium and myometrium resected; (ii) histological stage of the endometrium at the time of operation; (iii) rate of amenorrhoea; and (iv) patient satisfaction 1 year post-operatively. Each patient was reviewed in the out-patient clinic 3 months post-operatively. A questionnaire was sent to each patient 1 year after the operation. This questionnaire requested information on the patients' menstrual loss and pattern as well as overall satisfaction by asking whether they were disappointed, pleased or very pleased with the outcome of the procedure.
Statistical analysis
Discrete variables were analysed using Fisher's exact test and continuous variables using the MannWhitney U-test.
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Results |
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Histological details
The most common endometrial appearance (46%) associated with amenorrhoea was an inactive stage (Table I). This was most commonly found in women pre-treated with danazol and nafarelin, two groups which produced very different rates of amenorrhoea (see below) (Table II
). There were, however, no significant differences in the number of inactive endometria produced by each pre-treatment.
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Discussion |
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One of the claimed benefits of endometrial pre-treatment is the production of a thin endometrium at the time of operation. However, at follow-up, there was no significant difference in the median endometrial thickness between those women still menstruating and those who were amenorrhoeic. Further, although a greater median endometrial and myometrial thickness was noted in the control group when compared with groups receiving pre-treatment, there were no significant differences in the associated rates of amenorrhoea.
Pre-treatment with danazol resulted in significantly higher rates of amenorrhoea than the other medical pre-treatments. Although danazol has also been reported to be associated with high rates of amenorrhoea, better results have been noted with the gonadotrophin-releasing hormone (GnRH) agonists, leuprorelide acetate or goserelin (Brooks and Serden, 1991; Serden and Brooks, 1992
; Sutton and Ewen, 1994
; Garry et al., 1996
). However, in this study, significantly higher rates of amenorrhoea were found in those women pre-treated with danazol than in those pre-treated with the GnRH agonist nafarelin. In contrast to the previous findings (Romer and Schwesinger, 1997
), no significant difference in rates of amenorrhoea were noted between danazol and the control group.
Inactive endometrium was the most common histological stage associated with amenorrhoea at 1 year. Similar findings have been reported previously (Alford and Hopkins, 1996). However, although danazol and nafarelin were associated with a similar incidence of inactive endometrial glands and stroma, they were associated with significantly different rates of amenorrhoea. This difference could not be accounted for by a significant difference in median endometrial or myometrial thickness. Furthermore, a significantly higher rate of amenorrhoea was observed in the inactive, compared with the secretory, group. This is in contrast to previous findings (Hellen et al., 1993
) from a study of women undergoing TCRE who were pre-treated with danazol. This group reported that there was no difference in clinical outcome between those women in whom the endometrium was active or inactive at the time of operation. The disappointing results obtained with MPA may, in part, be explained by the ability of progestagens, e.g. Depot Provera, to induce vascular proliferation and neovascularization without atrophic changes in the endometrium (Brooks et al., 1991
). This unpredictable effect of Depo Provera may also account for the variable histological findings in the endometria in this group. Findings of more spiral arterioles than expected in the early proliferative phase and dysynchrony between the histological appearances of the endometrial glands and stroma of patients with menorrhagia compared with that seen in patients without menorrhagia have previously been described (Brooks et al., 1991
). The findings of similar dysynchrony in some patients in the control group in this study may be a reflection of their underlying abnormality which results in menorrhagia.
The high satisfaction rates observed are similar to those described by others (O'Connor and Magos, 1996; Steffensen and Schuster, 1997
). The reasons for failure in those women who underwent subsequent hysterectomy, namely worsening of dysmenorrhoea, persistent menorrhagia and pre-menstrual pelvic pain, were comparable to those previously described (Unger and Meeks, 1996
).
In conclusion, no improvement in clinical outcome or patient satisfaction is conferred by the use of medical pre-treatments if TCRE is performed in the proliferative phase of the menstrual cycle. This avoids the need to treat patients pre-operatively with drugs that may be expensive and sometimes have unpleasant side-effects. Although no improvement in clinical outcome or patient satisfaction was observed, other benefits of pre-treatment such as decreased fluid absorption and operating time together with better operative conditions were not studied. In addition, it is not always practical to arrange for this procedure to be performed in the proliferative phase of the menstrual cycle, not only because of the unpredictability of each woman's cycle but also because of the need to arrange the date of admission several weeks in advance. Medical pre-treatments may therefore still be of value in women undergoing TCRE by facilitating scheduling of the procedure.
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Notes |
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References |
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Submitted on December 9, 1999; accepted on May 9, 2000.