90 YEARS OF PROGESTERONE: Selective progesterone receptor modulators in gynaecological therapies

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Abstract

Abnormal uterine bleeding (AUB) is a chronic, debilitating and common condition affecting one in four women of reproductive age. Current treatments (conservative, medical and surgical) may be unsuitable, poorly tolerated or may result in loss of fertility. Selective progesterone receptor modulators (SPRMs) influence progesterone-regulated pathways, a hormone critical to female reproductive health and disease; therefore, SPRMs hold great potential in fulfilling an unmet need in managing gynaecological disorders. SPRMs in current clinical use include RU486 (mifepristone), which is licensed for pregnancy interruption, and CDB-2914 (ulipristal acetate), licensed for managing AUB in women with leiomyomas and in a higher dose as an emergency contraceptive. In this article, we explore the clinical journey of SPRMs and the need for further interrogation of this class of drugs with the ultimate goal of improving women’s quality of life.

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Uterine fibroid management: from the present to the future

Jacques Donnez, Marie-Madeleine Dolmans (2016)

Abstract Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Clinical presentations include abnormal bleeding, pelvic masses, pelvic pain, infertility, bulk symptoms and obstetric complications. Almost a third of women with leiomyomas will request treatment due to symptoms. Current management strategies mainly involve surgical interventions, but the choice of treatment is guided by patient's age and desire to preserve fertility or avoid ‘radical’ surgery such as hysterectomy. The management of uterine fibroids also depends on the number, size and location of the fibroids. Other surgical and non-surgical approaches include myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization and interventions performed under radiologic or ultrasound guidance to induce thermal ablation of the uterine fibroids. There are only a few randomized trials comparing various therapies for fibroids. Further investigations are required as there is a lack of concrete evidence of effectiveness and areas of uncertainty surrounding correct management according to symptoms. The economic impact of uterine fibroid management is significant and it is imperative that new treatments be developed to provide alternatives to surgical intervention. There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids due to the use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate (UPA). The efficacy of long-term intermittent use of UPA was recently demonstrated by randomized controlled studies. The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs which are proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids.

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Ulipristal acetate versus placebo for fibroid treatment before surgery.

Jacques Donnez, Tetyana Tatarchuk, Philippe Bouchard … (2012)

The efficacy and safety of oral ulipristal acetate for the treatment of symptomatic uterine fibroids before surgery are uncertain. We randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of >100 on the pictorial blood-loss assessment chart [PBAC, an objective assessment of blood loss, in which monthly scores range from 0 to >500, with higher numbers indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g per deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) or to receive placebo (48 women). All patients received iron supplementation. The coprimary efficacy end points were control of uterine bleeding (PBAC score of <75) and reduction of fibroid volume at week 13, after which patients could undergo surgery. At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of ulipristal acetate, 92% of those receiving 10 mg of ulipristal acetate, and 19% of those receiving placebo (P<0.001 for the comparison of each dose of ulipristal acetate with placebo). The rates of amenorrhea were 73%, 82%, and 6%, respectively, with amenorrhea occurring within 10 days in the majority of patients receiving ulipristal acetate. The median changes in total fibroid volume were -21%, -12%, and +3% (P=0.002 for the comparison of 5 mg of ulipristal acetate with placebo, and P=0.006 for the comparison of 10 mg of ulipristal acetate with placebo). Ulipristal acetate induced benign histologic endometrial changes that had resolved by 6 months after the end of therapy. Serious adverse events occurred in one patient during treatment with 10 mg of ulipristal acetate (uterine hemorrhage) and in one patient during receipt of placebo (fibroid protruding through the cervix). Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently than with placebo. Treatment with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids. (Funded by PregLem; ClinicalTrials.gov number, NCT00755755.).

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Ulipristal acetate versus leuprolide acetate for uterine fibroids.

Jacques Donnez, Janusz Tomaszewski, Francisco Vázquez … (2012)

The efficacy and side-effect profile of ulipristal acetate as compared with those of leuprolide acetate for the treatment of symptomatic uterine fibroids before surgery are unclear. In this double-blind noninferiority trial, we randomly assigned 307 patients with symptomatic fibroids and excessive uterine bleeding to receive 3 months of daily therapy with oral ulipristal acetate (at a dose of either 5 mg or 10 mg) or once-monthly intramuscular injections of leuprolide acetate (at a dose of 3.75 mg). The primary outcome was the proportion of patients with controlled bleeding at week 13, with a prespecified noninferiority margin of -20%. Uterine bleeding was controlled in 90% of patients receiving 5 mg of ulipristal acetate, in 98% of those receiving 10 mg of ulipristal acetate, and in 89% of those receiving leuprolide acetate, for differences (as compared with leuprolide acetate) of 1.2 percentage points (95% confidence interval [CI], -9.3 to 11.8) for 5 mg of ulipristal acetate and 8.8 percentage points (95% CI, 0.4 to 18.3) for 10 mg of ulipristal acetate. Median times to amenorrhea were 7 days for patients receiving 5 mg of ulipristal acetate, 5 days for those receiving 10 mg of ulipristal acetate, and 21 days for those receiving leuprolide acetate. Moderate-to-severe hot flashes were reported for 11% of patients receiving 5 mg of ulipristal acetate, for 10% of those receiving 10 mg of ulipristal acetate, and for 40% of those receiving leuprolide acetate (P<0.001 for each dose of ulipristal acetate vs. leuprolide acetate). Both the 5-mg and 10-mg daily doses of ulipristal acetate were noninferior to once-monthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes. (Funded by PregLem; ClinicalTrials.gov number, NCT00740831.).

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Author and article information

Journal

Journal ID (nlm-ta): J Mol Endocrinol

Journal ID (iso-abbrev): J. Mol. Endocrinol

Journal ID (hwp): JME

Title: Journal of Molecular Endocrinology

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 0952-5041

ISSN (Electronic): 1479-6813

Publication date Collection: July 2020

Publication date (Electronic): 30 January 2020

Volume: 65

Issue: 1

Pages: T15-T33

Affiliations

[1 ]MRC Centre for Reproductive Health , The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh Bioquarter, Edinburgh, UK

Author notes

Correspondence should be addressed to H O D Critchley: Hilary.Critchley@ 123456ed.ac.uk

This review forms part of a special section on 90 years of progesterone. The guest editors for this section are Dr Simak Ali, Imperial College London, UK, and Dr Bert W O’Malley, Baylor College of Medicine, USA.

Article

Publisher ID: JME-19-0238

DOI: 10.1530/JME-19-0238

PMC ID: 7354704

PubMed ID: 32599565

SO-VID: 3a2d82ca-ad97-4a8b-80cb-c1f529134b4f

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This work is licensed under a Creative Commons Attribution 4.0 International License.

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90 YEARS OF PROGESTERONE: Selective progesterone receptor modulators in gynaecological therapies

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Most cited references 116

Uterine fibroid management: from the present to the future

Ulipristal acetate versus placebo for fibroid treatment before surgery.

Ulipristal acetate versus leuprolide acetate for uterine fibroids.

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