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).