Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial.

Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

Historical Perspectives and Evolution of Menstrual Terminology.

Abnormal uterine bleeding (AUB) in the reproductive years in non-pregnant women comprises a group of symptoms that include abnormal frequency and the irregular onset of flow as well as prolonged and heavy menstrual bleeding. It is a common, chronic, and debilitating condition affecting women worldwide with an adverse impact on their quality of life. Until the last decade, the "menstrual" terminology used to describe both normal and abnormal uterine bleeding and its underlying causes was inconsistent, creating considerable confusion. Using standardized terminology may potentially improve clinical management as well as help designing and interpreting basic, translational, epidemiological, and clinical research in women with menstrual problems. In this article, we explore the history and evolution of menstrual terminology and discuss the two International Federation of Gynecology and Obstetrics (FIGO) systems on i.e., (A) menstrual terminology and definitions (B) and the causes of AUB, achieved through international consensus of relevant stakeholders through a long multistage journey.

Uterine bleeding: how understanding endometrial physiology underpins menstrual health.

Menstruation is a physiological process that is typically uncomplicated. However, up to one third of women globally will be affected by abnormal uterine bleeding (AUB) at some point in their reproductive years. Menstruation (that is, endometrial shedding) is a fine balance between proliferation, decidualization, inflammation, hypoxia, apoptosis, haemostasis, vasoconstriction and, finally, repair and regeneration. An imbalance in any one of these processes can lead to the abnormal endometrial phenotype of AUB. Poor menstrual health has a negative impact on a person's physical, mental, social, emotional and financial well-being. On a global scale, iron deficiency and iron deficiency anaemia are closely linked with AUB, and are often under-reported and under-recognized. The International Federation of Gynecology and Obstetrics have produced standardized terminology and a classification system for the causes of AUB. This standardization will facilitate future research endeavours, diagnosis and clinical management. In a field where no new medications have been developed for over 20 years, emerging technologies are paving the way for a deeper understanding of the biology of the endometrium in health and disease, as well as opening up novel diagnostic and management avenues.

The endometrial response to modulation of ligand-progesterone receptor pathways is reversible.

OBJECTIVE: To study the impact of the progesterone receptor modulator (PRM), ulipristal acetate (UPA), on endometrial morphology and function. DESIGN: Cross-sectional. SETTING: University Research Institute. PATIENT(S): Endometrial biopsies from 16 patients with heavy menstrual bleeding with a structurally normal uterus or in association with structural abnormalities identified on radiological imaging (fibroids, adenomyosis or a combination of fibroids and adenomyosis). INTERVENTION(S): Participants received UPA (5 mg once daily) for three 12-week courses, each separated by 4 weeks without treatment. MAIN OUTCOME MEASURE(S): Gene expression by real-time quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and digital image analysis were analyzed to investigate the endometrial impact of modulation of progesterone receptor pathways upon expression of steroid receptors, steroid metabolizing enzymes, cell proliferation, and progesterone-regulated genes in the same patients at 3 time points: before, during, and after discontinuation of PRM treatment. RESULT(S): Ulipristal acetate treatment resulted in increased messenger ribonucleic acid (mRNA) levels of steroid receptors compared with pretreatment secretory endometrium; decreased mRNA levels of 17- and 11-beta-hydroxysteroid dehydrogenases compared with pretreatment proliferative endometrium and pretreatment secretory endometrium; reduced cell proliferation compared with pretreatment proliferative endometrium; and altered mRNA levels of progesterone-regulated genes. A strong consistency between immunohistochemistry-digital image analysis and real-time quantitative reverse transcription polymerase chain reaction results was evident. Alterations in the mRNA levels and endometrial morphology returned to a pretreatment phenotype after the cessation of PRM exposure. CONCLUSION(S): The endometrial impact of the modulation of progesterone receptor pathways with PRM (UPA) treatment is reversible. CLINICAL TRIAL REGISTRATION NUMBER: Ulipristal acetate versus conventional management of heavy menstrual bleeding (UCON) trial (EudraCT 2014-003408-65; REC14/LO/1602).

Misoprostol vaginal insert versus dinoprostone vaginal insert: A comparison of labour and delivery outcomes.

OBJECTIVES: To compare Misoprostol Vaginal Insert (MVI), a vaginal insert containing 200 µg of misoprostol) versus Dinoprostone Vaginal Insert (DVI), a vaginal insert containing 10 mg of dinoprostone), in the induction of labour. STUDY DESIGN: We performed a retrospective analysis of the data between February 2016 and September 2017 of women induced with MVI (n = 100) and DVI in UK (n = 100) at NHS Fife. MVI was used for the same indications as DVI, but specifically indicated in women with a Modified Bishops score ≤ 4. Outcome measures included: the incidence of tachysystole and hyperstimulation; further use of prostaglandins; use of pre-delivery oxytocin; mode of delivery; median insertion-to-delivery-interval; and admission to the neonatal unit. Statistical data analysis was performed. A logistic regression analysis was also performed, adjusting for potential confounders such as body mass index (BMI), gestational age, parity and baseline Modified Bishops score. RESULTS: Demographics such as parity, BMI, baseline Modified Bishops score and gestational age were assessed. A significantly higher rate of tachysystole and hyperstimulation was noted in the MVI group as compared to the DVI group. Only 8% of women in the MVI group as compared to a third (33%) of women in the DVI group required further prostaglandins. There was no difference in the modes of birth in either group and this result was statistically significant. The median induction to delivery interval was 15 h in the MVI group compared to 33 h in the DVI group. There was no difference in neonatal outcomes in either group. There was no significant difference in the use of pre-delivery oxytocin for subsequent augmentation of labour in either group. All the results, when adjusted to potential confounders using logistic regression, were in keeping with the unadjusted statistical analysis. CONCLUSION: The results of this study suggest that MVI significantly reduces the induction to delivery interval, has a similar caesarean section rate and neonatal outcomes, when compared with DVI.

Biomarkers in abnormal uterine bleeding†.

Abnormal uterine bleeding (AUB) is an extremely common problem and represents a clinical area of unmet need. It has clinical implications and a high cost for the healthcare system. The PALM-COEIN acronym proposed by FIGO may be used as a foundation of care; it improves the understanding of the causes of AUB, and in doing so facilitates effective history taking, examination, investigations, and management. Heavy menstrual bleeding, a subset of AUB, is a subjective diagnosis and should be managed in the context of improving the woman's quality of life. Available evidence suggests that there is poor satisfaction with standard treatment options often resulting in women opting for major surgery such as hysterectomy. Such women would benefit from a tailored approach, both for diagnosis and treatment, highlighting the deficiency of biomarkers in this area. This article focuses on the causes of AUB as per the PALM-COEIN acronym, the researched biomarkers in this area, and the potential pathogenetic mechanisms. In the future, these approaches may improve our understanding of AUB, thereby enabling us to direct women to most suitable current treatments and tailor investigative and treatment strategies to ensure best outcomes, in keeping with the principles of personalized or precision medicine.

Synthetic osmotic dilators in the induction of labour-An international multicentre observational study.

INTRODUCTION: To evaluate the effects of synthetic osmotic dilators (Dilapan-S/ Dilasoft) in women who required induction of labour in a large prospective multicentre international observational study. MATERIALS AND METHODS: Primary outcomes were duration of Dilapan-S/Dilasoft insertion (hours), total induction - delivery interval (hours) and the rate of vaginal deliveries within 24 h (%). Secondary outcomes were the number of dilators inserted, Bishop score increase after extraction of Dilapan-S/Dilasoft, complications during induction (uterine contractions, uterine tachysystole and hyperstimulation, effect on the fetus) and post induction (infections and neonatal outcomes), agents / procedures used for subsequent induction of labour, immediate rate of spontaneous labours following cervical ripening period, rate of spontaneous vaginal deliveries, rate of instrumental vaginal deliveries and caesarean sections. RESULTS: Total of 543 women were recruited across 11 study sites, of which, 444 women were eligible for analysis. With Dilapan-S/Dilasoft use of <12 h (n = 188) the overall vaginal delivery rate was 76.6% with 45.7% of these births occurring within 24 h, 66% within 36 h and 75.5% within 48 h from insertion of Dilapan-S/Dilasoft. The mean insertion-delivery interval for this group was 24.3(±10.4) hours. With Dilapan-S/Dilasoft use of >12 h (n = 256), the overall vaginal delivery rate was 64.8%, with 16% of these births occurring within 24 h, 48.4% within 36 h and 54.7% within 48 h from insertion of Dilapan-S/Dilasoft. The mean insertion-delivery interval for this group was 39.1(±29.2) hours. The mean gain in the Bishops score was +3.6(±2.3). The mean number of Dilapan-S/Dilasoft dilators used was 3.8 (±1.1). The overall rate of caesarean section was 30.1%. The overall complication rate was low including infection risk. No adverse neonatal outcome was attributable to the use of Dilapan-S/Dilasoft. CONCLUSION: Dilapan-S/Dilasoft are safe and effective methods for cervical ripening. Their use is associated with low maternal and neonatal complication rates. Future research should aim at level I clinical trials comparing Dilapan-S to other mechanical or pharmacological cervical ripening agents. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02318173.

Synthetic osmotic dilators for cervical preparation prior to abortion-An international multicentre observational study.

OBJECTIVES: To evaluate the outcomes with the use of Dilapan-S for cervical preparation prior to medical or surgical abortion. STUDY DESIGN: International, multicentre, prospective observational study in women between 6 + 0-24 + 0 weeks' gestation. The study was conducted across 7 study sites in 4 countries, between 1/5/2015 to 31/12/2016. The primary outcomes studied were the number of dilators used and the duration required for cervical preparation prior to abortion. Secondary outcomes were complications of dilator use and infection. Participants were followed-up for 4 weeks post procedure to capture any delayed complications. RESULTS: A total of 483 women were enrolled with 439 women eligible for analysis. Medical abortion was performed in 38% (n = 165) women and surgical abortion in 62% (n = 274). For medical abortions and surgical abortions, an average of 3 osmotic dilators for time interval of 4-7 hours provided effective cervical preparation. Medical abortions were performed as day-case procedures (<12 h) in 81% of women. There was no difference in using either adjunctive misoprostol or Dilapan-S followed by misoprostol for cervical ripening effect to achieve complete medical abortion. Dilapan-S permitted surgical abortions to be performed as same-day procedures (<12 h), in 85% of women regardless of gestational age and without the need to use adjunctive or additional misoprostol. There were no serious adverse events reported with the use of Dilapan-S, including in women with a previous caesarean section. The overall infectious morbidity was 0.9% of cases with no causal relationship with the use of synthetic osmotic dilator use (for a length <24 h). In addition, Dilapan-S was reported as easy to insert and remove in over 90% of women. CONCLUSION: Dilapan-S is a safe and effective method for cervical preparation for medical and surgical abortions up to 24 weeks' gestation. It allows medical and surgical abortions to be performed as day case procedures and is associated with a low complication rate. Future research should aim at directly comparing Dilapan-S and preferred pharmacological agents in a randomised controlled trial.

Endometrial ablation for heavy menstrual bleeding.

Endometrial ablation can be described as one of the great gynecological success stories. It has changed the management of heavy menstrual bleeding dramatically. The development of newer (second generation) endometrial ablative techniques has enabled clinicians to set up comprehensive 'one stop clinics' based on an outpatient service to treat heavy menstrual bleeding effectively without the need for general anesthetic or conscious sedation. This article describes the rationale and evidence for use of different endometrial auto-ablative systems along with relevant technical and clinical aspects. It also addresses the essentials of a successful approach to outpatient endometrial ablation along with discussion on risks, complications and contraindications of the procedure.