Is endometrial pre-treatment of value in improving the outcome of transcervical resection of the endometrium?

V.S. Rai,, M.D.G. Gillmer and W. Gray

1 Department of Obstetrics and Gynaecology, and 2 Department of Cellular Pathology, John Radcliffe Hospital, Headington, Oxford, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The aim of this study was to determine whether or not the use of medical pre-treatment of the endometrium improves the outcome of transcervical resection of the endometrium with regards to long-term operative outcome, histological findings and patient satisfaction. A prospective randomized trial comparing three endometrial pre-treatment agents (danazol, medroxyprogesterone acetate or nafarelin) with no pre-treatment was conducted. The main outcome measures were: (i) thickness of the endometrium and myometrium resected; (ii) histological stage of the endometrium at the time of operation; (iii) the presence or absence of menses and (iv) patient satisfaction 1 year post-operatively. Of the three pre-treatments studied, danazol produced a lower median endometrial thickness than the control, showed the greatest ability to induce atrophy of the endometrial glands and stroma (not statistically significant) and produced the highest rate of amenorrhoea (not different to the control). Danazol and nafarelin produced significantly lower median endometrial thickness than no pre-treatment. There were, however, no significant differences in the rates of amenorrhoea in any of the pre-treatment groups compared with that in the control group. No improvement in clinical outcome or patient satisfaction is conferred by the use of medical pre-treatments if transcervical resection of the endometrium is performed in the proliferative phase of the menstrual cycle.

Key words: endometrium/pre-treatment/resection


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Transcervical resection of the endometrium (TCRE) for dysfunctional uterine bleeding and menorrhagia is performed in >10 000 women per year in England and Wales (O'Connor and Magos, 1996Go). The advantages of this technique over hysterectomy (a shorter operating time and hospital stay with improved cost-effectiveness, quicker recovery and return to work) have been well documented (Sculpher et al., 1996Go; O'Connor et al., 1997Go; Nagele et al., 1998Go; Sulpher, 1998).

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, 1997Go; Seeras and Gilliland, 1997Go). 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., 1994Go, 1996Go; Donnez et al., 1997Go; Sorrensen et al., 1997Go). 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., 1992Go). In support of this is the finding of endometrium in hysterectomy specimens of women who have undergone unsuccessful endometrial resections (McCulloch et al., 1995Go).

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., 1991Go). 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, 1994Go; Garry et al., 1996Go).

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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study was an open randomized prospective trial comparing the use of either Danazol, medroxyprogesterone acetate (MPA, Provera®; Pharmacia & Upjohn, Milton Keynes, UK) or naferelin (Synarel®; Searle, High Wycombe, Bucks, UK) prior to TCRE with performing the procedure in the early proliferative phase of the menstrual cycle without pre-treatment. In order to detect a significant difference in amenorrhoea rates of 25% with no pre-treatment and 50% with pre-treatment, with a power of 70%, 100 women would need to be recruited. Data were collected between 1992 and 1996.

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 Mann–Whitney U-test.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 100 women were randomized in equal numbers to the four pre-treatment groups. No patient withdrew from the study after randomization. For follow-up assessment, a written reminder and second questionnaire had to be sent to 22 patients and a further eight patients needed to be contacted by telephone after failing to respond to the second questionnaire. There were no cases of uterine perforation and no women required a blood transfusion. In all, 94 patients were discharged on the day of their operation and six stayed in hospital overnight.

Histological details
The most common endometrial appearance (46%) associated with amenorrhoea was an inactive stage (Table IGo). 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 IIGo). There were, however, no significant differences in the number of inactive endometria produced by each pre-treatment.


View this table:
[in this window]
[in a new window]
 
Table I. Relationship between rates of amenorrhoea and histological stage of the endometrium. Values in parentheses are percentages
 

View this table:
[in this window]
[in a new window]
 
Table II. Histological stage of the endometrium resulting from each pre-treatment. Values in parentheses are percentages
 
The median endometrial and myometrial thicknesses produced by each of the pre-treatment groups are given in Table IIIGo. There was no significant difference in the endometrial thickness between those women rendered amenorrhoeic and those who were not. Danazol and nafarelin produced the lowest median endometrial thickness. This was significantly lower than that found in the control group. Interestingly, although the second highest rates of amenorrhoea were observed in those women who received no pre-treatment, a higher median endometrial thickness was also seen in this group. There was no significant difference in the median myometrial thickness in the group of women who were amenorrhoeic compared with those who were still having menses. The median myometrial thickness in the control group was, however, significantly greater than in the groups pre-treated with danazol and nafarelin.


View this table:
[in this window]
[in a new window]
 
Table III. Relationship between thickness of the endometrium and myometrium, clinical outcome and type of pre-treatment. Values are given as medians with the range in parentheses
 
Menstrual details after TCRE
A total of 46 women reported complete amenorrhoea. The relationship between pre-treatment and rates of amenorrhoea is shown in Table IVGo. Danazol produced the highest rates of amenorrhoea and its use was significantly more commonly associated with amenorrhoea compared with MPA and nafarelin. However, no significant difference was noted between the rates of amenorrhoea in those women pre-treated with danazol and the control group.


View this table:
[in this window]
[in a new window]
 
Table IV. Relationship between rates of amenorrhoea and endometrial pre-treatment. Values in parentheses are percentages
 
Patient satisfaction
Of the study group, 78% were very pleased, 17% pleased and 5% disappointed with the outcome of the procedure. There was no significant difference in satisfaction rates between the pre-treatment groups (Table VGo). All five women who expressed disappointment were pre-treated with nafarelin. The main reasons for disappointment were worsening of dysmenorrhoea and pre-menstrual pain. When asked if they would recommend the procedure to friends with heavy periods, 91% said yes, 5% that they didn't know and 4% said no. There were no significant differences in the responses to this question between the pre-treatment groups.


View this table:
[in this window]
[in a new window]
 
Table V. Patient satisfaction and pre-treatment groups. Values in parentheses are percentages
 
Patients needing further treatment
Two women (one in the MPA group and one in the control group) reported that they had needed further medical treatments, in the form of non-steroidal anti-inflammatory agents, for menorrhagia. Four women subsequently underwent hysterectomy (two pre-treated with danazol and two pre-treated with nafarelin). The reasons for hysterectomy were worsening of dysmenorrhoea and pre-menstrual pelvic pain and, in one case, persistent menorrhagia.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Pre-treatment of the endometrium does not increase the rate of amenorrhoea or patient satisfaction when compared with performing the procedure after the cessation of menstruation. Of the medical pre-treatments studied, danazol gave the highest rate of amenorrhoea (not different form control), a lower median endometrial thickness than the control and the highest rates of inactive changes of the endometrium (not signficant).

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, 1991Go; Serden and Brooks, 1992Go; Sutton and Ewen, 1994Go; Garry et al., 1996Go). 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, 1997Go), 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, 1996Go). 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., 1993Go) 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., 1991Go). 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., 1991Go). 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, 1996Go; Steffensen and Schuster, 1997Go). 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, 1996Go).

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.


    Notes
 
3 To whom correspondence should be addressed at: Level 4, Women's Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. E-mail: vrai77{at}hotmail.com Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Alford, W.S. and Hopkins, M.P. (1996) Endometrial rollerball ablation. J. Reprod. Med., 41, 251–254.[ISI][Medline]

Brooks, P.G. and Serden, S.P. (1991) Preparation of the endometrium for ablation with a single dose of leuprolide acetate depot. J. Reprod. Med., 36,477–478.[ISI][Medline]

Brooks, P.G., Serden, S.P. and Davos, I. (1991) Hormonal inhibition of the endometrium for resectoscopic endometrial ablation. Am. J. Obstet. Gynecol., 164, 1601–1606.[ISI][Medline]

Donnez, J., Vilos, G., Gannon, M.J. et al. (1997) Goserelin acetate (Zoladex) plus endometrial ablation for dysfunctional uterine bleeding: a large randomized, double-blind study. Fertil. Steril., 68, 29–36.[ISI][Medline]

Garry, R., Khair, A., Mooney, P.A. et al. (1996) A comparison of goserelin and danazol as endometrial thinning agents prior to endometrial laser ablation. Br. J. Obstet. Gynaecol., 103, 339–344.[ISI][Medline]

Hellen, E.A., Coghill, S.B. and Shaxted, E.J. (1993) The histopathology of transcervical resection of the endometrium: an analysis of 200 cases. Histopathology, 22, 361–365.[ISI][Medline]

Magos, A.L., Baumann, R., Lockwood, G.M. et al. (1991) Experience with the first 250 endometrial resections for menorrhagia. Lancet, 337, 1074–1078.[ISI][Medline]

McCulloch, T.A., Wagner, B., Duffy, S. et al. (1995) The pathology of hysterectomy specimens following transcervical resection of the endometrium. Histopathology, 27, 541–547.[ISI][Medline]

Nagele, F., Rubinger, T. and Magos, A. (1998) Why do women choose endometrial ablation rather than hysterectomy? Fertil. Steril., 69, 1063–1066.[ISI][Medline]

O'Connor, H. and Magos, A. (1996) Endometrial resection for the treatment of menorrhagia. N. Engl J. Med., 335, 151–156.[Abstract/Free Full Text]

O'Connor, H., Broadbent, J.A., Magos, A.L. et al. (1997) Medical Research Council randomised trial of endometrial resection versus hysterectomy in managment of menorrhagia. Lancet, 349, 897–901.[ISI][Medline]

Reid, P.C., Thurrell, W., Smith, J.H. et al. (1992) Nd:YAG laser endometrial ablation: histological aspects of uterine healing. Int. J. Gynecol. Pathol., 11,174–179.[ISI][Medline]

Romer, T. and Schwesinger, G. (1997) Hormonal inhibition of endometrium for transcervical endometrial ablation – a prospective study with a 2-year follow-up. Eur. J. Obstet. Gynecol. Reprod. Biol., 74, 201–203.[ISI][Medline]

Sculpher, M.J. (1998) The cost-effectiveness of preference-based treatment allocation: the case of hysterectomy versus endometrial resection in the treatment of menorrhagia. Health Econ., 7, 129–142.[ISI][Medline]

Sculpher, M.J., Dwyer, N., Byford, S. et al. (1996) Randomised trial comparing hysterectomy and transcervical endometrial resection: effect on health related quality of life and costs two years after surgery. Br. J. Obstet. Gynaecol., 103, 142–149.[ISI][Medline]

Seeras, R.C. and Gilliland, G.B. (1997) Resumption of menstruation after amenorrhoea in women treated by endometrial ablation and myometrial resection. J. Am. Assoc. Gynecol. Laparosc., 4, 305–309.[ISI][Medline]

Serden, S.P. and Brooks, P.G. (1992) Preoperative therapy in preparation for endometrial ablation. J. Reprod. Med., 37, 679–681.[ISI][Medline]

Sorrensen, S.S., Colov, N.P. and Vejerslev, L.O. (1997) Pre- and post-operative therapy with GnRH agonist for endometrial resection. A prospective, randomised study. Acta Obstet. Gynecol. Scand., 76, 340–344.[ISI][Medline]

Steffensen, A.J. and Schuster, M. (1997) Endometrial resection and late reoperation in the treatment of menorrhagia. J. Am. Assoc. Gynecol. Laparosc., 4, 325–329.[ISI][Medline]

Sutton, C.J. and Ewen, S.P. (1994) Thinning the endometrium prior to ablation: is it worthwhile? Br. J. Obstet. Gynaecol., 101 (Suppl. 10), 10–12.[ISI][Medline]

Unger, J.B. and Meeks, G.R. (1996) Hysterectomy after endometrial ablation. Am. J. Obstet. Gynecol., 175,1432–1436.[ISI][Medline]

Vercellini, P., Trespidi, L., Bramante, T. et al. (1994) Gonadotropin releasing hormone agonist treatment before hysteroscopic endometrial resection. Int. J. Gynaecol. Obstet., 45, 235–239.[ISI][Medline]

Vercellini, P., Perino, A., Consonni, R. et al. (1996) Treatment with a gonadotrophin releasing hormone agonist before endometrial resection: a multicentre, randomised controlled trial. Br. J. Obstet. Gynaecol., 103, 562–568.[ISI][Medline]

Submitted on December 9, 1999; accepted on May 9, 2000.





This Article
Abstract
FREE Full Text (PDF )
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Request Permissions
Google Scholar
Articles by Rai, V.S.
Articles by Gray, W.
PubMed
PubMed Citation
Articles by Rai, V.S.
Articles by Gray, W.