Introduction

The clinical problem

Heavy menstrual bleeding (HMB) affects one in four women of reproductive age and has a profound effect on quality of life.1 The burden of HMB is significant2,3 and prompts 1 million women in the UK to seek help for their symptoms annually.4 HMB is responsible for the loss of 5 million workdays in the UK,5 while globally, direct and indirect treatment costs amount to US$1 billion and $12 billion annually.6

The previous objective measurement definition of HMB as > 80 ml of blood per menses has been superseded by the more patient centred ‘excessive menstrual blood loss which interferes with a woman’s physical, social, emotional, and/or material quality of life’ proposed by National Institute for Health and Care Excellence (NICE) and adopted by the Menstrual Disorders Group of the International Federation of Gynecology and Obstetrics.7 The underlying mechanism of HMB is multifactorial and is broadly classified into structural (including uterine fibroids) and non-structural causes.7 However, rather than a classification-driven, precision-based approach, present-day management of HMB is driven by other factors, including age, desire for fertility preservation, clinician and patient preference.8

Treatment for heavy menstrual bleeding

Current management options include conservative treatment (wait and watch), medical or surgical (endometrial ablation and hysterectomy) approaches. Medical treatments for HMB predominantly target the progesterone receptor (PR). The levonorgestrel-releasing intrauterine system (LNG-IUS) is recommended by NICE as the first-line medical treatment; alternatives include other progestin-containing pharmacological agents, gonadotrophin-releasing analogues (GnRHa), or non-hormonal options such as cyclooxygenase inhibitors and anti-fibrinolytic therapy.9

Existing medical treatments for HMB are not effective in, or acceptable to, all women. While first-line treatment with the LNG-IUS substantially reduces menstrual blood loss, often resulting in amenorrhoea, unscheduled bleeding may be problematic, with up to one-third ceasing use within 2 years.10 The invasive nature of the insertion of the device also limits its acceptability11 and, while not a contradiction per se (unless distorting the endometrial cavity), the presence of fibroids may increase expulsion rates.12 Other hormonal treatments incur the risk of irregular unpredictable spotting/bleeding, mood swings, hot flushes and weight gain, which may impact compliance.13,14

GnRHa induce oestrogen deficiency, which reduces bone density and causes vasomotor symptoms. These side effects limit long-term use of GnRHa. Non-hormonal treatments may also be discontinued due to side effects as well as lack of efficacy.15 Overall, of those women accessing medical treatments, up to 77% of women on oral drugs and 20–42% of those using the LNG-IUS will undergo surgery within five years.16 In the absence of fibroids, surgery for HMB is limited to endometrial ablation or hysterectomy. While both surgical modalities are effective at delivering bleeding control and improving quality of life,17 neither is compatible with future fertility. For many women with HMB, fertility conserving treatment is growing in importance, in keeping with the rising age of first childbirth in the UK and elsewhere.

Selective progesterone receptor modulators: utility and mechanism

A group of pharmacological agents, the selective progesterone receptor modulators (SPRMs), have potential utility to provide an effective oral treatment for HMB. SPRMs bind with PRs, resulting in tissue-specific effects in both myometrial and overlying endometrial tissue as well as direct effects on uterine fibroids.18 In addition, SPRM administration results in anovulation in up to 80% of women despite maintenance of circulating estradiol concentrations in the mid-follicular range.19,20

Though the degree of progesterone receptor antagonism varies depending on the specific class member,21 treatment with the SPRMs mifepristone, asoprisnil and ulipristal acetate (UPA) has shown efficacy in reducing fibroid size and affording control of bleeding compared with a placebo.22 Although no single agent is more effective than another,22 UPA is the only SPRM to have been licensed for clinical use, albeit prescription has been restricted to women with symptomatic fibroids.9 In women with uterine fibroids ranging from 3 to 10 cm in size treated with UPA, control of HMB was achieved in over 90% of women treated with UPA and amenorrhoea reported in 70%, although the mechanism through which the bleeding control is achieved remains poorly understood.23,24 Reported side effects were limited to minor complaints such as headache and breast tenderness.23,24

UPA has the potential to be an effective, fertility-sparing, convenient oral treatment for HMB. However, there are uncertainties regarding the mechanism and location of action of UPA, as well as longer-term safety and effectiveness. SPRMs induce distinctive, non-physiological endometrial changes, which can be confused with endometrial hyperplasia.25 This specific histological phenotype is termed progesterone receptor modulator-associated endometrial change (PAEC) and is present in 41–79% of women treated with SPRMs.26,27 Despite mid-follicular range circulating estradiol concentrations and relative progesterone antagonism within the endometrium,28 these morphological changes do not appear to be associated with endometrial hyperplasia or malignant change.29 Indeed UPA administration is associated with reduction in endometrial cell proliferation,28 and histology returns to normal after discontinuation of treatment.25,26 However, the mechanisms underlying these changes and their clinical significance remains unclear.

Recently there has been concern regarding the potential for UPA to cause liver injury (i.e. drug-induced liver injury or DILI). Post marketing surveillance reports to the European Medicines Authority (EMA) Pharmacovigilance Risk Assessment Committee resulted in a temporary halt in UPA use in 201830 and 2020.31 Use of UPA has been reinstated since January 2021, albeit in a restricted context,9 reflecting the paucity of existing alternatives for HMB.32

Rationale for study

HMB remains a clinical area of unmet need, with high prevalence, marked adverse impacts on quality of life and a significant socioeconomic burden. There is an urgent need to develop effective, safe, acceptable and affordable fertility-sparing medical treatments for HMB that can be taken orally, whether associated with fibroids or not. SPRMs may provide a solution in light of the mounting evidence that progesterone and the PR play a pivotal role in both menstruation and fibroid growth and development. Studies in women with larger fibroids have demonstrated that UPA is well tolerated and can deliver effective control of bleeding in most women. However, despite its therapeutic potential, robust data on the long-term effectiveness and the mechanisms of action of SPRMs in women with HMB remained unknown. There was an urgent need to evaluate the use of UPA against current best medical treatment for all women with HMB. Further understanding of the impact of UPA on the endometrium and liver was also required to inform the role of SPRMs to treat HMB in context of existing medical treatments.

Study objectives

The objectives of the UCON study were specified in the trial protocol, available at https://www.fundingawards.nihr.ac.uk/award/12/206/52.

Clinical objectives

The primary objective of the randomised controlled trial was to determine whether UPA is more effective at reducing the burden of HMB symptoms than LNG-IUS after 12 months of treatment.

The secondary objectives were as follows:

1. 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.
2. 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.
3. 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.
4. 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:

1. Alters endometrial cell function, (e.g., and not limited to, proliferation, apoptosis, expression of steroid receptors, tumour suppressors and inflammatory mediators).
2. Reduces blood plasma flow in the endometrium, uterine myometrium and fibroid tissue.
3. Alters the volume fraction of the extracellular matrix in the above tissues.
4. Reduces uterine and fibroid volume.