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Abstract Background Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Recurrence of symptoms following an operation is common. Although hormonal treatment can reduce this risk, there is uncertainty about the best option. Objectives To evaluate the clinical and cost-effectiveness of long-acting progestogen therapy compared with the combined oral contraceptive pill in preventing recurrence of endometriosis-related pain and quality of life. Design A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women’s lived experience of endometriosis and a pretrial economic model. Setting Thirty-four United Kingdom hospitals. Participants Women of reproductive age undergoing conservative surgery for endometriosis. Interventions Long-acting progestogen reversible contraceptive (either 150 mg depot medroxyprogesterone acetate or 52 mg levonorgestrel-releasing intrauterine system) or combined oral contraceptive pill (30 µg ethinylestradiol, 150 µg levonorgestrel). Main outcome measures The primary outcome was the pain domain of the Endometriosis Health Profile-30 questionnaire at 36 months post randomisation. The economic evaluation estimated the cost per quality-adjusted life-years gained. Results Four hundred and five women were randomised to receive either long-acting reversible contraceptive (N = 205) or combined oral contraceptive pill (N = 200). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no difference between the two (adjusted mean difference: −0.8, 95% confidence interval −5.7 to 4.2; p = 0.76). The long-acting reversible contraceptive group underwent fewer surgical procedures or second-line treatments compared with the combined oral contraceptive group (73 vs. 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). The mean adjusted quality-adjusted life-year difference between two arms was 0.043 (95% confidence interval −0.069 to 0.152) in favour of the combined oral contraceptive pill, although this cost an additional £533 (95% confidence interval 52 to 983) per woman. Limitations Limitations include the absence of a no-treatment group and the fact that many women changed treatments over the 3 years of follow-up. Use of telephone follow-up to collect primary outcome data in those who failed to return questionnaires resulted in missing data for secondary outcomes. The COVID pandemic may have affected rates of further surgical treatment. Conclusions At 36 months, women allocated to either intervention had comparable levels of pain, with both groups showing around a 40% improvement from presurgical levels. Although the combined oral contraceptive was cost-effective at a threshold of £20,000 per quality-adjusted life-year, the difference between the two was marginal and lower rates of repeat surgery might make long-acting reversible contraceptives preferable to some women. Future work Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence. Trial registration This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information. The NIHR recognises that people have diverse gender identities, and in this report, the word ‘woman’ is used to describe patients or individuals whose sex assigned at birth was female, whether they identify as female, male or non-binary. Plain language summary What was the question? Endometriosis is a condition where cells similar to ones that line the womb are found elsewhere in the body. Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Unfortunately, symptoms often return and some women will need repeat operations. Hormonal contraceptives can prevent the return of endometriosis-related pain: either long-acting reversible contraceptives (injections or a coil, fitted inside the womb) or the combined oral contraceptive pill (often called ‘the pill’). We do not know which is the best option. The aim of this trial was to find out which of these two hormone treatments was more effective in terms of symptom relief, avoidance of further surgery and costs. What did we do? Four hundred and five women with endometriosis, who were not intending to get pregnant, participated in a clinical trial. Half of the participants took long-acting reversible contraceptives, and the other half took the pill for 3 years following endometriosis surgery. The choice of treatment was made at random by a computer to ensure a fair comparison, although those allocated to the long-acting contraceptive could choose between injections or the coil. Participants completed questionnaires about their symptoms and life quality at intervals up to 3 years. What did we find? Both treatments were equally good at reducing pain but more women using the pill had repeat operations. The pill was a little more costly overall but associated with a slightly higher quality of life. What does this mean? Both treatments are equally effective in reducing pain up to 3 years after surgery for endometriosis. The differences in costs are small and the choice of treatment should be based on personal preference. Scientific summary Background Endometriosis, which affects up to 1 in 10 women, is characterised by the proliferation of endometrial cells outside the uterus, usually within the pelvis. These endometriotic deposits undergo cyclical proliferation in response to ovarian oestrogen, resulting in internal bleeding, scarring and adhesion formation, which causes pain and has a serious impact on quality of life in affected women. Surgical removal or destruction of endometriotic tissue is currently the preferred treatment but the risk of recurrence is high. Recurrence can be controlled by post-surgical hormonal treatment to reduce circulating levels of oestrogen but there is uncertainty as to the clinical and cost-effectiveness of two commonly used modalities: long-acting reversible contraceptive (LARC) and the combined oral contraceptive pill (COCP). Progestogen-based LARCs used in the trial were the levonorgestrel-releasing intrauterine system (LNG-IUS) or depot medroxyprogesterone acetate injection (DMPA). Objectives To evaluate the clinical and cost-effectiveness of LARCs compared with COCP in preventing recurrence of endometriosis-related pain and quality of life. Design A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women’s lived experience of endometriosis and a pretrial economic model. Setting Thirty-four NHS hospitals within the UK. Participants Women of reproductive age undergoing laparoscopic surgery for pelvic pain due to endometriosis were eligible if they fulfilled the following criteria: Inclusion criteria: Aged 16–45 years. No immediate plans to conceive. Scheduled for laparoscopic conservative surgery, or diagnostic laparoscopy with concurrent surgery if endometriosis is found, for pelvic pain associated with endometriosis. Willing to be randomised to one long-acting progestogen (LNG-IUS or DMPA) and COCP. The following women were also eligible if they had recurrent pain and were to have conservative surgery for endometriosis: Had one or more previous diagnostic laparoscopies. Had previous laparoscopic conservative surgery for endometriosis, provided that this did not involve rectovaginal dissection or bowel resection. Used postoperative medical treatment, including the treatment options included in the trial. Previous use of treatment options included in the trial as contraceptives. Use of preoperative gonadotropin-releasing hormone analogues (GnRHa), provided that this was stopped at least 4 weeks prior to laparoscopy. Exclusion criteria: No endometriosis identified at diagnostic laparoscopy. Infertility. Any plans for further elective endometriosis surgery (for deep disease or endometrioma). Contraindications to the use of hormonal treatment with oestrogen or progestogens. Suspicion of malignancy. Interventions Four hundred and five women were randomised in a one-to-one ratio via secure internet facility to either LARCs or COCP. The LARC was either 150 mg DMPA or 52 mg LNG-IUS. The COCP formulation contained 30 µg ethinylestradiol and 150 µg levonorgestrel. The LARC (LNG-IUS or DMPA) was selected before randomisation by the patient if a preference was apparent (or alternatively allocated randomly if there was no opinion). Outcome measures Primary outcome Pain as evaluated by the pain domain of the Endometriosis Health Profile – 30-item (EHP-30) questionnaire at 36 months post randomisation. Secondary outcomes (evaluated at 6 months, 1, 2 and 3 years): The four core domains of the EHP-30 questionnaire (control and powerlessness; emotional well-being; social support; self-image). The six modular domains of the EHP-30 (work; relationships with family; sexual relationships; feelings about medical profession; feelings about treatment; feelings about infertility). Pelvic pain measured by visual analogue scale (VAS) during periods; during intercourse; at any time. Responses to the question ‘compared to 1 month ago, would you say your pelvic pain has “Got much better”, “Got a little better”, “Not changed much”, “Got worse”’. Fatigue, as measured by Fatigue Severity Scale (FSS) score. Menstrual regularity. Generic quality of life questionnaire [EuroQol-5 Dimensions, five-level version (EQ-5D-5L)], including index and thermometer scores. Capabilities, as a measure of well-being (ICEpop CAPability, ICECAP measure). Further therapeutic surgery or second-line treatment for endometriosis as a proxy for recurrence or ‘treatment failure’, defined as having undergone hysterectomy, surgery for endometriosis, laparoscopy or taking GnRHa treatment. Discontinuation rates of randomised treatment (time to first treatment change), with reasons for change. Serious adverse events. The economic evaluation estimated the cost per quality-adjusted life-years (QALYs) gained. Sample size To detect an 8-point difference on the EHP-30 pain domain with 90% power (p = 0.05) and assuming the standard deviation (SD) to be 22 points required 160 participants per group, 320 in total. To account for any loss to follow-up (estimated to be 20%), this target was inflated to 400. Eight points is equivalent to 0.36 SD, which can be considered halfway between a small (0.2 SD) to moderate (0.5 SD) effect size. This size of sample would also give us good power (80%) to detect a 10-point difference in the two stratified analyses of LNG-IUS versus COCP and DMPA versus COCP provided that these subgroups had a roughly even split. Results A total of 405 women were allocated to receive either LARC (N = 205) or COCP (N = 200) following laparoscopic surgery for endometriosis. The two randomised groups were comparable in terms of age [29.6 years (6.7 years) vs. 29.3 years (6.6 years)]; body mass index [27.0 kg/m2 (10.6 kg/m2) vs. 26.3 kg/m2 (5.5 kg/m2)]; early-stage endometriosis: stages I and II (79% vs. 79%); complete surgical excision (92% vs. 90%); white ethnicity (91% vs. 92%) and previous hormonal treatment (27% vs. 23%). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no statistically significant difference between LARC and COCP at 3 years [adjusted mean difference: −0.8; 95% confidence interval (CI) −5.7 to 4.2; p = 0.76]. The choice of LARC (LNG-IUS or DMPA) did not alter these findings. Most of the other domains of the EHP-30 were improved in both groups at all time points compared with preoperative scores, with no consistent evidence of any difference between groups when estimates of uncertainty were considered. Women in the LARC group had fewer surgical procedures or second-line treatments compared with those taking COCP (73 vs. 97 events, occurring in 50 vs. 61 women due to repeat interventions), translating to a 33% reduction in time to treatment failure [hazard ratio (HR) 0.67, 95% CI 0.44 to 1.00]. Participants in the LARC group had a slightly higher mean EQ-5D-5L score at 36 months compared with those in the COCP arm (0.693 and 0.686, respectively). The mean adjusted imputed QALY difference between the two arms was 0.043 (95% CI −0.069 to 0.152) in favour of COCP, where participants in LARC group had a lower QALY value than those randomised to COCP (1.937 and 1.976, respectively). Despite this, the COCP group was estimated to be more expensive than the LARC group by £533 (95% CI 52 to 983) per woman over 36 months of follow-up. Limitations In the absence of a no-treatment arm, we were unable to demonstrate the effect of surgery alone on preventing recurrence of pain symptoms. While we are able to comment on the effectiveness of a strategy of postoperative prescription of LARC versus COCP, the true impact of these interventions is difficult to gauge as the prolonged duration of follow-up meant that many women had discontinued their allocated treatments. The predominance of white women in the recruited sample limits our ability to be confident about how our results might apply to women from other ethnic backgrounds. Use of telephone follow-up to collect primary outcome data in those who failed to return full questionnaires resulted in missing data for some of the secondary outcomes. While all patients were recruited prior to the COVID-19 pandemic, the number of women who required further surgery may be underestimated, given the negative impact of COVID-19 on waiting lists for elective surgery throughout the UK. It is possible that this may have led to an increase in the use of GnRHa treatment by women who were unable to access surgery for their symptoms. Conclusions At 36 months, women allocated to LARCs or COCP had comparable levels of pain, with both groups showing around 40% improvement from presurgical levels. Although COCP is likely to be considered more cost-effective at a threshold of £20,000 per QALY, the difference between the two is marginal. LARCs may be preferred by some women as they are associated with lower rates of surgery, particular hysterectomy and operations for recurrence of endometriosis. Future work Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence. Active measures need to be adopted to improve the inclusivity of clinical research and ensure that the ethnic mix within participants mirror that of the general population. Trial registration This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information.

Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. The levonorgestrel-releasing intrauterine system is an effective long-term treatment but is discontinued by many due to unpredictable bleeding, or adverse effects. The selective progesterone receptor modulator ulipristal acetate is used to treat symptomatic fibroids but long-term efficacy for the symptom of heavy menstrual bleeding, irrespective of presence of fibroids, is unknown. Objectives To determine whether ulipristal acetate is more effective at reducing the burden of heavy menstrual bleeding than levonorgestrel-releasing intrauterine system after 12 months of treatment in women with and without fibroids. We investigated mechanism of action of ulipristal acetate in a subset of 20 women. Design Randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Setting Ten UK hospitals. Participants Women with heavy menstrual bleeding aged 18 and over with no contraindications to levonorgestrel-releasing intrauterine system or ulipristal acetate. Interventions Three 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or continuous levonorgestrel-releasing intrauterine system following allocation in a 1 : 1 ratio using a web-based minimisation procedure. Main trial outcome measures Primary outcome was quality-of-life measured by menorrhagia multi-attribute scale at 12 months. Secondary outcomes included menstrual bleeding and patient satisfaction. Impact on fibroid size, endometrial appearance and liver function was also collected. Mechanistic study outcome Cellular markers for endometrial cell structure and function, determined from endometrial biopsies; volume of uterus and fibroids and microcirculation parameters were determined from magnetic resonance images. Results Sample size was increased from 220 to 302 as a result of temporary halt to recruitment due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate and the COVID-19 pandemic led to a premature closure of recruitment, with 118 women randomised to each treatment and 103 women completing 12-month menorrhagia multi-attribute scale scores prior to this point. Primary outcome scores substantially improved in both arms, but at 12 months there was no evidence of a difference between those receiving three cycles of ulipristal acetate [median score category: 76–99, interquartile range (51–75 to 100), n = 53] and levonorgestrel-releasing intrauterine system [median score category: 76–99, interquartile range (51–75 to 100), n = 50; adjusted odds ratio 0.55, 95% confidence interval 0.26 to 1.17; p = 0.12]. Rates of amenorrhoea were much higher in those allocated ulipristal acetate compared with the levonorgestrel-releasing intrauterine system (12 months: 64% vs. 25%, adjusted odds ratio 7.12, 95% confidence interval 2.29 to 22.2). There was no evidence of a difference in other participant-reported outcomes. There were no cases of endometrial malignancy and no hepatotoxicity due to ulipristal acetate use. Mechanistic study results Ulipristal acetate produced a reversible reduction in endometrial cell proliferation, as well as reversible alteration of other endometrial cellular markers. Ulipristal acetate did not produce a reduction in the volume of the uterus irrespective of coexisting fibroids, nor an effect on uterine microvascular blood flow. Limitations The urgent safety measures and premature closure of recruitment impacted final sample size. Conclusions We found no evidence of a difference in quality of life between the two treatments, but ulipristal acetate was superior to levonorgestrel-releasing intrauterine system at inducing amenorrhoea. Ulipristal acetate currently has restricted availability due to concerns regarding hepatotoxicity. Future work There is a need to develop new, safe, effective and fertility-sparing medical treatments for heavy menstrual bleeding. The observed acceptability and effectiveness of ulipristal acetate warrants further research into the selective progesterone receptor modulator class of pharmacological agents. Study registration This trial is registered as ISRCTN 20426843. Plain language summary What is the problem? Heavy menstrual bleeding is a common condition that affects the lives of many women. A hormone-releasing coil, fitted inside the womb, is effective in making periods lighter but can make them less regular. A medicine called ulipristal acetate or UPA, taken as a pill, has been shown to reduce rapidly menstrual bleeding in women with large, non-cancerous tumours in the womb, known as fibroids. It was not known whether UPA is effective in women who have heavy periods but do not have fibroids of any significant size. What did we plan to do? To find out which treatment was better at controlling heavy periods, 236 women were enrolled in a clinical trial where they received either the hormone coil or UPA. The choice of treatment was made at random by a computer rather than the wishes of researchers or patients, to ensure a fair comparison. Participants completed questionnaires about their symptoms and life quality at intervals up to 1 year. Twice during the trial, medicines regulatory authorities raised safety concerns about UPA causing liver problems. This resulted in the introduction of regular blood tests. The second time, recruitment to the trial stopped early. What did we find? Both treatments improved the symptoms of heavy menstrual bleeding in the majority of women. We found no evidence that UPA was better overall after 1 year of treatment, compared with the hormone coil, although fewer women on UPA continued to have periods. Laboratory studies on samples taken from the lining of the womb showed temporary changes due to UPA, which disappeared after treatment stopped. What does this mean? Both treatments improve the symptoms of menstrual bleeding and general wellbeing. Because of safety concerns UPA is not available for all women with heavy menstrual bleeding and new, safer medical treatments are needed. Scientific summary Background Heavy menstrual bleeding (HMB) is the most common gynaecological problem in women of reproductive age, affecting one in four women, and has adverse profound impact on health-related quality of life. Common causes of HMB include structural abnormalities such as uterine fibroids, adenomyosis and dysfunction of the endometrium. The levonorgestrel-releasing intrauterine system (LNG-IUS) is a proven, effective long-term treatment but about one-third of women cease use by two years due to unpredictable bleeding, hormonal adverse effects or lack of effectiveness. Furthermore, fibroids can make the LNG-IUS less effective. Alternative medical options for HMB exist, but are either less effective or associated with unacceptable adverse effects. Surgical interventions are effective at inducing bleeding control and improving quality of life but are typically incompatible with future fertility. Effective long-term medical treatments for women with HMB are needed. A class of drugs called selective progesterone receptor modulators (SPRMs) have potential to provide an effective oral treatment for HMB. SPRMs bind with progesterone receptors, resulting in tissue-specific effects in both myometrial and overlying endometrial tissue as well as shrinking uterine fibroids. The SPRM ulipristal acetate (UPA) has been successfully used to treat fibroids, but we do not know how effective UPA is for the treatment of women with HMB who do not have fibroids. Furthermore, there are uncertainties regarding the mechanism and location of action of UPA, as well as its longer-term safety. SPRMs induce distinctive, non-physiological endometrial changes, which can be confused with endometrial hyperplasia. More recently there has been concern regarding the potential for UPA to cause drug-induced liver injury (DILI). Post marketing surveillance reports resulted in a temporary halt in UPA use in 2018 and 2020. Use of UPA has since been reinstated since January 2021, albeit in a restricted context, reflecting the paucity of existing alternatives for HMB. Given these uncertainties, we designed the UCON trial to evaluate the safety, tolerability and effectiveness of UPA on HMB and to understand its mechanism of action. Clinical objectives Primary objective: to determine whether UPA is more effective at reducing the burden of HMB symptoms than LNG-IUS after 12 months of treatment. Secondary objectives: Ascertain whether UPA use beyond 3 months’ and up to 12 months’ duration is associated with histological changes to the endometrium and, if so, whether this compromises safety. Ascertain whether UPA is more effective than LNG-IUS in relation to menstrual blood loss, sexual activity, generic quality of life, satisfaction with treatment, patient-reported adverse events, and compliance at 3, 6 and 12 months. Determine the response to UPA and LNG-IUS treatment difference in the presence of uterine fibroids in terms of (1) alleviation of HMB and (2) change in uterine/fibroid volume. Collect data on liver function in women taking UPA, once safety concerns were raised. Mechanism of action study objectives To understand how UPA causes a reduction in menstrual bleeding and uterine/fibroid volume in women with HMB, we determined whether UPA administration: Alters endometrial cell function (e.g., and not limited to, proliferation, apoptosis, expression of steroid receptors, tumour suppressors and inflammatory mediators). Reduces blood plasma flow in the endometrium, uterine myometrium and fibroid tissue. Alters the volume fraction of the extracellular matrix in these tissues. Reduces uterine and fibroid volume. Design This was a randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Methods Setting The trial recruited participants in 10 sites in NHS hospital settings across the UK between 2015 and 2020. The mechanism of action study was conducted solely at the Edinburgh site. Participants For the main trial, informed consent was sought from premenopausal women (aged 18–50 years) with self-reported HMB, no contraindications to LNG-IUS or UPA. Those with uterine size greater than equivalent 14-week size or with submucosal fibroids >2cm were excluded. Other exclusion criteria relating to use of other treatments and current health status were applied, including history of severe hepatic impairment. Screening and randomisation Participants were recruited in gynaecology clinics by research nurses who screened patient referral letters. Following consent, haemoglobin and circulating estradiol levels were assessed, clinical history elicited and transvaginal and/or abdominal ultrasound and endometrial biopsy were obtained if not previously performed. Following this, and confirmation of eligibility, randomisation was via a web-based central service based at Birmingham Clinical Trials Unit to allocate women in a 1 : 1 ratio using a minimisation algorithm. Screened patients in Edinburgh were offered the opportunity to participate in the mechanistic study. Interventions and follow-up Those allocated to UPA received three courses of treatment, each course comprising a daily 5-mg oral dose for 12 weeks followed by a four-week break. Those allocated to the LNG-IUS had it fitted in hospital or primary care. Participants allocated to UPA returned to hospital to collect their repeat prescription at 3 and 6 months, and may have been seen by a member of the care team if required. They were then seen in clinic at 12 months for ultrasound scan (USS) and haemoglobin/serum estradiol measurement. Those allocated to the LNG-IUS group attended USS at 12 months. Follow-up at interim time points was conducted by postal questionnaire. Those partaking in the mechanism of action study underwent magnetic resonance imaging (MRI) following randomisation and at the end of treatment cycles two and three. An additional endometrial biopsy was obtained at the end of treatment cycle two. Outcome measures Primary Condition-specific quality of life score as measured by the menorrhagia multi-attribute scale (MMAS) questionnaire at 12 months. Summary scores range from 0 (worst affected) to 100 (not affected). Secondary Condition-specific quality of life score as measured by MMAS at 3 and 6 months Menstrual bleeding (pictorial blood loss assessment chart)* Cycle regularity (ordinal four-point scale)* Duration of period (ordinal three option scale)* Pelvic pain during periods, intercourse and at other times (visual analogue scales; 0 = best outcome, 10 = worse outcome)* Uterine fibroid symptom and quality of life instrument (only given to women diagnosed with fibroids)* Sexual function (sexual activity questionnaire)* Generic quality of life (EQ-5D-5L)* Satisfaction with treatment outcome (five-point Likert scale) Participant rating of effect of treatment on HMB over 12 months (four-point Likert scale) Whether participant is willing to recommend the treatment to a friend (yes/no) Surgical intervention Adherence to trial treatments and reasons for changing treatment, as reported by the participant Serious adverse events and reactions Uterine volume, evidence of adenomyosis, presence of fibroids, largest fibroid volume, endometrial thickness, endometrial appearance, evidence of ovarian cysts at 12 months (USS) Endometrial biopsy at 12 months (UPA group only) Liver function tests, from 20 March 2018 every four weeks (UPA group only) Haemoglobin and serum estradiol at 12 months * assessed at 3, 6 and 12 months Mechanism of action A: Effects on cellular markers of endometrial steroid receptors and metabolising enzymes (governing local endometrial steroid [ligand] availability), cell proliferation, cell survival (apoptosis); detection of genes implicated in control of proliferation in endometrium; B: Effects on uterine/fibroid structure addressed by obtaining volume measurements for the whole uterus, and for the total volume of fibroids when present, by using high resolution structural MRI and stereology; and C: Uterine vascularity using dynamic contrast-enhanced MRI (DCE-MRI). Urgent safety measures In November 2017, the European Medicines Agency (EMA) issued an urgent drug alert for UPA due to a small number of reports of serious liver injury. A detailed investigation by the regulatory authorities was undertaken and it was found that eight reports of serious liver injury were reported in Europe from an estimated 740,000 women using UPA for uterine fibroids. Restrictions on prescribing UPA were subsequently issued and the trial sponsor implemented an urgent safety measure (USM) in February 2018, which halted recruitment. Those allocated UPA were allowed to complete their current course of UPA treatment but not commence any further outstanding courses. In addition, they commenced monthly assessment of LFTs (as well as a post treatment test approximately 2 weeks after the last course of UPA). In August 2018, the halt on UPA prescribing was lifted and recruitment to UCON resumed in October 2018 with additional safety measures in place, including exclusion of those with any history of liver disease [defined as levels of alanine transaminase (ALT) or aspartate aminotransferase (AST) of more than two times the upper limit of normal] and LFT monitoring as described above. UPA was stopped if women had an ALT or AST more than three times the upper limit of normal and a hepatology opinion was sought. In March 2020, the EMA temporarily suspended use of UPA a second time due to ongoing concerns regarding hepatotoxicity and a further USM was issued. All treatment courses of UPA were immediately stopped. In view of the second USM, the investigators, in discussion with the funder, chose premature closure of recruitment to the study but planned follow-up actions continued as per protocol. Statistical considerations The study was powered to detect a clinically useful difference in MMAS score (13 points) between the two groups at twelve months. To detect a difference of this size [0.5 standard deviations (SDs)] with 90% power (p = 0.05) would require 86 women in each group (172 in total). To allow for a 20% loss to follow-up or pregnancy, the sample size was inflated to 220 women. Following the initial USM, this figure was inflated to 302 women to ensure that there were adequate responses in the primary analysis population (defined below) to detect the same size of difference. The original planned primary analysis population comprised all participants, regardless of adherence to treatment, employing suitable regression models to estimate difference between groups. The enforced non-compliance as a result of the withdrawal of UPA had substantial implications for the validity of the data reported by participants. It was therefore necessary to redefine analysis populations, considering the restrictions that prevented women taking their courses of UPA might influence their responses and any other new potential biases that may be apparent in either group due to, for example, knowledge of the safety concerns around UPA. The primary analysis population would now comprise participants with questionnaire responses received prior to the first USM (12 February 2018), along with questionnaire responses from participants recruited following the study restart (18 October 2018) provided that the responses were returned before the second USM (17 March 2020). Results Main trial A total of 4471 women were approached for the study, with 236 consented and randomised, of whom 181 (77%) returned primary outcome data at 12 months (103 within the primary analysis population). Baseline data were comparable between groups; 92% were white, 34% had fibroids and 8% adenomyosis. In the primary analysis population, MMAS scores substantially improved in both arms, but at 12 months there was no evidence of a difference between the UPA [median score category: 76–99, IQR (51–75 to 100), n = 53] and LNG-IUS [median score category: 76–99, IQR (51–75 to 100), n = 50] groups (adjusted OR 0.55, 95% CI 0.26 to 1.17; p = 0.12). Rates of amenorrhoea where much higher in those allocated UPA compared with LNG-IUS at each time point (3 months: 56% vs. 5%, adjusted OR 29.3, 95% CI 7.37 to 116; 6 months 53% vs. 10%, adjusted OR 11.7 95% CI 3.78 to 36.0; 12 months: 64% vs. 25%, adjusted OR 7.12, 95% CI 2.29 to 22.2). There was no evidence of a difference in the other patient-reported outcomes although there was considerable uncertainty. In those with uterine fibroids, there were no changes in fibroid or uterine volume in either treatment group at 12 months. On endometrial biopsy, seven participants (8%) had evidence of progesterone receptor modulator associated endometrial changes (PAEC) at 12 months, although none was observed at a further 6 months post treatment; there were no cases of endometrial malignancy. Rates of serious adverse events were low, and no patients required admission to hospital for management of deranged liver function tests due to UPA use. Mechanism of action study Effects of UPA administration on the uterus: UPA produced a reduction in cell proliferation in the endometrium, as well as alteration of other local endometrial cellular markers (steroid receptor and steroid metabolising enzyme expression) creating a local endometrial oestrogenic environment. The effects on endometrial cellular markers were reversed upon withdrawal of UPA treatment. Stereological analysis in 19 patients showed that UPA did not produce a reduction in the volume of the uterus, irrespective of coexisting fibroids or adenomyosis. DCE-MRI in 15 patients showed that UPA appears not to have an effect on uterine blood flow. If adenomyosis was present in the uterus, there was a significant increase in plasma volume in the endometrium. However, one of the five women with adenomyosis also had fibroids. Effects of UPA administration on uterine fibroids: DCE-MRI studies showed that UPA produced an average reduction in plasma volume in 11 fibroids, which may be interpreted as being due to a reduction in extracellular matrix components. This finding was not supported by stereological analysis, which failed to show a reduction in the total volume of fibroids in eight patients. However, it should be noted that the number of subjects studied is small. Conclusions Both UPA and LNG-IUS alleviated the adverse impact of heavy menstrual bleeding on quality of life but we found no evidence of a difference between groups over 12 months. UPA was evidently superior to LNG-IUS in terms of inducing amenorrhoea. We observed no difference in reduction in the volume of the uterus, whether or not fibroids were present and no difference in change in the volume of fibroids was observed. Analysis of selected markers of endometrial cellular function demonstrated UPA modulation of the progesterone receptor, resulting in molecular and cellular alteration in steroid receptors within the endometrium, consistent with the development of a local (endometrial) oestrogenic microenvironment. Despite this, there is no evidence of pathological endometrial changes. We demonstrated that alteration in the endometrial microenvironment reverses on cessation of UPA treatment, a key factor for a medical treatment of HMB, particularly for those who wish to preserve fertility. UPA now has restricted availability due to concerns regarding hepatotoxicity. Findings from this study may offer insights into mechanism of action of other SPRM class members. New, effective and acceptable oral medical treatment options are needed to address an important unmet clinical need. Recommendations for research Further studies of medical treatments for HMB Developing other SPRMs, not associated with DILI Other hormonal/non-hormonal medical treatments for HMB Patient populations that encompass both the symptoms of HMB and underlying aetiologies, including structurally normal uterus, adenomyosis and small fibroids Study design with outcome measures impact on menstrual bleeding pattern, pelvic pain and impact on haemoglobin and iron-deficiency, as well as quality of life Qualitative studies to determine what are the most important outcomes to women who suffer HMB Study registration This trial is registered as ISRCTN 20426843. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 8. See the NIHR Journals Library website for further project information.

Introduction There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique.Methods and analysis A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months’ postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities.Ethics and dissemination The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE.Trial registration number ISRCTN14566195.

Background: Heavy menstrual bleeding (HMB) is a common problem that affects many British women. When initial medical treatment is unsuccessful, the National Institute for Health and Care Excellence recommends surgical options such as endometrial ablation (EA) or hysterectomy. Although clinically and economically more effective than EA, total hysterectomy necessitates a longer hospital stay and is associated with slower recovery and a higher risk of complications. Improvements in endoscopic equipment and training have made laparoscopic supracervical hysterectomy (LASH) accessible to most gynaecologists. This operation could preserve the advantages of total hysterectomy and reduce the risk of complications. Objectives: To compare the clinical effectiveness and cost-effectiveness of LASH with second-generation EA in women with HMB. Design: A parallel-group, multicentre, randomised controlled trial. Allocation was by remote web-based randomisation (1 : 1 ratio). Surgeons and participants were not blinded to the allocated procedure. Setting: Thirty-one UK secondary and tertiary hospitals. Participants: Women aged 11 cm; any fibroids > 3 cm; contraindications to laparoscopic surgery; previous EA; and inability to give informed consent or complete trial paperwork. Interventions: LASH compared with second-generation EA. Main outcome measures: Co-primary clinical outcome measures were (1) patient satisfaction and (2) Menorrhagia Multi-Attribute Quality-of-Life Scale (MMAS) score at 15 months post randomisation. The primary economic outcome was incremental cost (NHS perspective) per quality-adjusted life-year (QALY) gained. Results: A total of 330 participants were randomised to each group (total n = 660). Women randomised to LASH were more likely to be satisfied with their treatment than those randomised to EA (97.1% vs. 87.1%) [adjusted difference in proportions 0.10, 95% confidence interval (CI) 0.05 to 0.15; adjusted odds ratio (OR) from ordinal logistic regression (OLR) 2.53, 95% CI 1.83 to 3.48; p

Objectives Declining clinical exposure in female pelvic examination, increasing student numbers and the intimate nature of the examination poses challenges for medical student training. This study explores the experience and acceptability of all stakeholders involved in a novel method of pelvic examination teaching with the use of expert patients called 'Gynaecological Teaching Associates' (GTAs). An additional aim was to ascertain the motivation of lay women to become GTAs. Methods A qualitative study was conducted with participants including medical students, teaching and non-teaching faculty members and GTAs. Data was collected through semi-structured interviews, a group interview with a supplemental interview, and non-participant observation (NPO). Twenty students, eight faculty staff, and four GTAs were interviewed, and NPO was accomplished during teaching sessions. Analysis Sequential thematic analysis was conducted on all transcripts. Data from both field notes and interview transcripts was triangulated to establish the validity of findings. Results Medical students found GTA teaching acceptable and reported an increased confidence in undertaking female pelvic examinations. They reported a lack of opportunities for male medical students to obtain exposure to, and experience of, gynaecological examination prior to the introduction of the GTA teaching. Other themes included overcoming the intimate nature of the examination, comparing manikin to GTA teaching, and the positive impact on clinical practice. Potential drawbacks included the perception of this "abnormal" teaching method amongst the general public. Lay women volunteered due to the rewarding nature of teaching and the benefit provided to the students. Conclusion GTA teaching has been described as a positive experience by all stakeholders. Acceptability has been established with positive outcomes noted for students. GTA motivation was noted to be altruistic. There are some concerns documented, especially the ability to recruit and monitor an effective GTA teaching programme, as well as to ensure the safety of the GTAs themselves.

Background: Uterine polyps cause abnormal bleeding in women and conventional practice is to remove them in hospital under general anaesthetic. Advances in technology make it possible to perform polypectomy in an outpatient setting, yet evidence of effectiveness is limited. Objectives: To test the hypothesis that in women with abnormal uterine bleeding (AUB) associated with benign uterine polyp(s), outpatient polyp treatment achieved as good, or no more than 25% worse, alleviation of bleeding symptoms at 6 months compared with standard inpatient treatment. The hypothesis that response to uterine polyp treatment differed according to the pattern of AUB, menopausal status and longer-term follow-up was tested. The cost-effectiveness and acceptability of outpatient polypectomy was examined. Design: A multicentre, non-inferiority, randomised controlled trial, incorporating a cost-effectiveness analysis and supplemented by a parallel patient preference study. Patient acceptability was evaluated by interview in a qualitative study. Setting: Outpatient hysteroscopy clinics and inpatient gynaecology departments within UK NHS hospitals. Participants: Women with AUB – defined as heavy menstrual bleeding (formerly known as menorrhagia) (HMB), intermenstrual bleeding or postmenopausal bleeding – and hysteroscopically diagnosed uterine polyps. Interventions: We randomly assigned 507 women, using a minimisation algorithm, to outpatient polypectomy compared with conventional inpatient polypectomy as a day case in hospital under general anaesthesia. Main outcome measures: The primary outcome was successful treatment at 6 months, determined by the woman’s assessment of her bleeding. Secondary outcomes included quality of life, procedure feasibility, acceptability and cost per quality-adjusted life-year (QALY) gained. Results: At 6 months, 73% (166/228) of women who underwent outpatient polypectomy were successfully treated compared with 80% (168/211) following inpatient polypectomy [relative risk (RR) 0.91, 95% confidence interval (CI) 0.82 to 1.02]. The lower end of the CIs showed that outpatient polypectomy was at most 18% worse, in relative terms, than inpatient treatment, within the 25% margin of non-inferiority set at the outset of the study. By 1 and 2 years the corresponding proportions were similar producing RRs close to unity. There was no evidence that the treatment effect differed according to any of the predefined subgroups when treatments by variable interaction parameters were examined. Failure to completely remove polyps was higher (19% vs. 7%; RR 2.5, 95% CI 1.5 to 4.1) with outpatient polypectomy. Procedure acceptability was reduced with outpatient compared with inpatient polyp treatment (83% vs. 92%; RR 0.90, 95% CI 0.84 to 0.97). There were no significant differences in quality of life. The incremental cost-effectiveness ratios at 6 and 12 months for inpatient treatment were £1,099,167 and £668,800 per additional QALY, respectively. Conclusions: When treating women with AUB associated with uterine polyps, outpatient polypectomy was non-inferior to inpatient polypectomy at 6 and 12 months, and relatively cost-effective. However, patients need to be aware that failure to remove a polyp is more likely with outpatient polypectomy and procedure acceptability lower. Trial registration: Current Controlled Trials ISRCTN 65868569. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 61. See the NIHR Journals Library website for further project information.

Background: Heavy menstrual bleeding (HMB) and post-menopausal bleeding (PMB) together constitute the commonest gynaecological presentation in secondary care and impose substantial demands on health service resources. Accurate diagnosis is of key importance to realising effective treatment, reducing morbidity and, in the case of PMB, reducing mortality. There are many tests available, including transvaginal scan (TVS), endometrial biopsy (EBx), saline infusion sonography and outpatient hysteroscopy (OPH); however, optimal diagnostic work-up is unclear. Objectives: To determine the most cost-effective diagnostic testing strategy for the diagnosis and treatment of (i) HMB and (ii) PMB. Data sources: Parameter inputs were derived from systematic quantitative reviews, individual patient data (IPD) from existing data sets and focused searches for specific data. In the absence of data estimates, the consensus view of an expert clinical panel was obtained. Methods: Two clinically informed decision-analytic models were constructed to reflect current service provision for the diagnostic work-up of women presenting with HMB and PMB. The model-based economic evaluation took the form of a cost-effectiveness analysis from the perspective of the NHS in a contemporary, ‘one-stop’ secondary care clinical setting, where all indicated testing modalities would be available during a single visit. Results: Two potentially cost-effective testing strategies for the initial investigation of women with HMB were identified: OPH alone or in combination with EBx. Although a combination testing strategy of OPH + EBx was marginally more effective, the incremental cost-effectiveness ratio (ICER) was approximately £21,000 to gain one more satisfied patient, whereas for OPH it was just £360 when compared with treatment with the levonorgestrel intrauterine system (LNG-IUS) without investigation. Initial testing with OPH was the most cost-effective testing approach for women wishing to preserve fertility and for women with symptoms refractory to empirical treatment with a LNG-IUS. For the investigation of PMB, selective use of TVS based on historical risk prediction for the diagnostic work-up of women presenting with PMB generated an ICER compared with our reference strategy of ‘no initial work-up’ of £129,000 per extra woman surviving 5 years. The ICERs for the two other non-dominated testing strategies, combining history and TVS or combining OPH and TVS, were over £2M each. Limitations: In the absence of IPD, estimates of accuracy for test combinations presented some uncertainty where test results were modelled as being discordant. Conclusions: For initial investigation of women presenting to secondary care with HMB who do not require preservation of their fertility, our research suggests a choice between OPH alone or a combination of OPH and EBx. From our investigation, OPH appears to be the optimal first-line diagnostic test used for the investigation of women presenting to secondary care with HMB wishing to preserve their fertility or refractory to previous medical treatment with the LNG-IUS. We would suggest that the current recommendation of basing the initial investigation of women with PMB on the universal TVS measurement of endometrial thickness at a 5-mm threshold may need to be replaced by a strategy of restricting TVS to women with risk factors (e.g. increasing age-raised body mass index, diabetes or nulliparity), obtained from the preceding clinical assessment. Funding: The National Institute for Health Research Health Technology Assessment programme.