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A Randomised Controlled Trial Comparing Gnrh Antagonist DOI: 10.1111/j.1471-0528.2008.01837.x Gynaecological surgery www.blackwellpublishing.com/bjog A randomised controlled trial comparing GnRH antagonist Cetrorelix with GnRH agonist Leuprorelin for endometrial thinning prior to transcervical resection of endometrium K Bhatia,a Y Doonan,b A Giannakou,c B Bentickd a Royal Blackburn Hospital, Blackburn, UK b Fertility Unit, Royal Shrewsbury Hospital, Shrewsbury, UK c Institute for Health Research, Lancaster University, Lancaster, UK d Royal Shrewsbury Hospital, Shrewsbury, UK Correspondence: Dr Kalsang Bhatia, 7 Whinney Hey’s Road, Blackpool, Lancashire, FY3 8NP, UK. Email [email protected] Accepted 2 June 2008 Objectives To compare the effectiveness of leuprorelin and both groups (80% cetrorelix and 84% leuprorelin) with no cetrorelix, when used as preoperative endometrial thinning agents statistical significance. All endometrial outcome measures prior to transcervical resection of endometrium (TCRE). including endometrial thickness on ultrasound, histology and operative appearance were more favourable in leuprorelin group as Design A prospective, double-blind randomised controlled trial. compared with cetrorelix (P values 0.013, <0.001 and 0.003 Setting Gynaecological department of a UK district general respectively). More women in leuprorelin group had hot flushes as hospital. compared with cetrorelix (15/50 versus 6/50; P = 0.047). No significant differences were seen in other outcome measures. Participants A total of 106 premenopausal women with dysfunctional uterine bleeding, undergoing TCRE. Conclusions In dosages used, leuprorelin produced more consistent thinning of the endometrium as compared with cetrorelix, although Interventions Women were equally randomised to 3.75 mg of this did not make any significant difference to operative or leuprorelin acetate (3–4 weeks) or 3 mg cetrorelix (4–7 days) prior menstrual outcomes. The endometrial thinning effect with cetrorelix to TCRE. About 1 ml saline was given as placebo in both arms. does appear to be more favourable than that seen at postmenstrual Main outcome measures Amenorrhoea rate at 6 months, phase in other studies. The optimum (possibly higher) dosage of endometrial thickness using transvaginal ultrasound on the day of cetrorelix for this purpose has not yet been established. operation. Keywords Cetrorelix, leuprorelin, endometrial preparation, TCRE, Results A total of 100 women completed the trial with no loss to randomised controlled trial. follow up. Amenorrhoea rate at 6 months after surgery was high in Please cite this paper as: Bhatia K, Doonan Y, Giannakou A, Bentick B. A randomised controlled trial comparing GnRH antagonist Cetrorelix with GnRH agonist Leuprorelin for endometrial thinning prior to transcervical resection of endometrium. BJOG 2008;115:1214–1224. Introduction time. Complete endometrial removal or destruction is one of the most important determinants of treatment success and Transcervical resection of endometrium (TCRE) is now a rec- therefore surgery is said to be most effective if undertaken ognised form of surgical treatment for women with dysfunc- when endometrial thickness is less than 4 mm, in the imme- tional uterine bleeding where medical treatment has failed. It diate post-menstrual phase.1 However, due to logistic prob- offers a less radical, day-case surgical alternative to hysterec- lems in reliably arranging surgery for this time, agents to tomy for these women. Although there has been a recent prepare the endometrium are frequently used prior to TCRE. insurgence of various second generation modalities of endo- Gonadotrophin-releasing hormone (GnRH) agonists are metrial ablation, where preoperative endometrial preparation currently the most commonly used endometrial thinning is generally not used, there is still a special place for TCRE, agents.2 They cause continuous stimulation of the GnRH which has a higher amenorrhoea rate in experienced hands receptor, producing an initial period of hypersecretion of and also allows submucous fibroids to be resected at the same typically 2 weeks followed quickly by pituitary desensitisation 1214 ª 2008 The Authors Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology Cetrorelix versus leuprorelin prior to TCRE and arrest of gonadotrophin secretion by a post-receptor administered at any phase of the menstrual cycle; the injection mechanism, which is still not clear.3 The initial hypersecretion was given 4–8 days before surgery in premenopausal women however, induces a ‘flare up’ effect, which is responsible for undergoing hysteroscopy or hysterectomy. Six women were in adverse effects such as premenstrual symptoms, and because the luteal phase and four in follicular phase. All but one of the period of pituitary desensitisation, it has to be given at woman had withdrawal bleeding of varying degrees within least 3 weeks preoperatively to obtain the desired effect on the 48 hours of the injection. The participant who did not have endometrium, thus making the treatment period longer. Up any withdrawal bleeding was in early follicular phase, with an to 25% of women on single dose of GnRH agonist and 64% of endometrial thickness (double layer) of 2.5 mm on transva- those on two doses suffer from hot flushes during the treat- ginal scanning (TVS). The double-layer endometrial thickness ment period.4 Hence, an ideal endometrial-thinning agent is for the others ranged from 2 to 7 mm when scanned up to 8 yet to be found.2 days of the injection. The serum estradiol and LH levels GnRH antagonists, unlike the agonistic analogues, do not remained suppressed up to the sixth day, being lowest on induce an initial stimulation of gonadotrophin release but day 4 as expected. We, therefore, concluded that a single sub- causes immediate and rapid, reversible and dose-dependent cutaneous dose of 3 mg cetrorelix when given 4–7 days before suppression of gonadotrophin secretion by competitive recep- TCRE could reliably induce withdrawal bleeding in most tor occupancy of GnRH receptor.5 As a result, the onset of women, possibly bringing about the desired effect on the action and treatment period is significantly shorter with endometrium as needed for the procedure. With this back- reduced incidence of adverse effects. GnRH antagonists are ground, we proceeded with the randomised controlled trial. now at an advanced stage of clinical development, with accept- able pharmacokinetics, safety and commercial profiles. They Methods are currently licensed only for use in assisted conception and prostatic cancer, although all other indications for GnRH ago- This prospective, double-blinded, randomised controlled trial nist desensitisation may also prove to be indications for GnRH was conducted in the Gynaecological Unit at the Royal antagonists. In fact, application in endometriosis, fibroids and Shrewsbury Hospital, between October 2003 and December gynaecological cancers are already being explored.6–8 Because 2005. The Shropshire Ethics Committee approved the study of their rapid and reversible effects, with shorter treatment and a woman was considered eligible for the study if she was period and better adverse-effect profile, GnRH antagonists premenopausal and had opted for TCRE following appropri- may have a promising role as preoperative endometrial thin- ate selection and counselling for failed medical treatment for ning agents. They can be easily administered during the pre- dysfunctional uterine bleeding. These women had normal operative assessment visit within 1 week of the operation, smear history, with no concurrent gynaecological problems thereby avoiding two visits to hospital or an extra visit at the and had no desire for further children. As per unit policy, primary care level. This would also allow for arrangement of women aged 40 years and above had endometrial biopsy per- operations at shorter notice, an advantage from convenience formed and those with clinically enlarged uterus also had point of view and also a welcome solution to the women as well a pelvic ultrasound scan. Women with uterine size equivalent as local general practitioners. However, there are no relevant to or more than 12 weeks of pregnancy, previous TCRE, those published studies to this date and so this study aimed to deter- with menopausal symptoms and significant medical problems mine their efficacy in endometrial thinning prior to TCRE. or severe allergic reactions were excluded from the study. Cetrorelix acetate is a potent, hypoallergenic GnRH antag- Those with submucous fibroids less than 5 cm and nonatyp- onistic analogue and was the first of its kind to be licensed for ical hyperplasia on endometrial biopsy were included in the clinical use. Clinical trials with cetrorelix in women have study. Women on hormonal medications or MIRENA inter- mostly been performed in relation to assisted conception uterine system (IUS) were advised to discontinue the treat- techniques where it is known to prevent a premature gonad- ment 3 months before the procedure and were prescribed otrophin surge in women undergoing controlled ovarian other nonhormonal preparations to control their bleeding. stimulation, allowing the follicles to mature for planned Suitable women for the trial were identified from the wait- oocyte collection.9–12 Phase 2 clinical trials have established ing list and consecutively from the menorrhagia clinic, with that the onset of luteinising hormone (LH) suppression is detailed patient information leaflets sent out after telephone approximately 1 hour with
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