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

Critchley HOD, Hilary Critchley, Chodankar RR, Rohan Chodankar
Journal of molecular endocrinology · 2020 · vol. 65(1) , pp. T15–T33 · doi:10.1530/jme-19-0238 · PMID:32599565 · PMC7354704 · W3037228576
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Selective progesterone receptor modulators (SPRMs) are explored as promising treatments for gynecological disorders like abnormal uterine bleeding, with current examples including mifepristone and ulipristal acetate.

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This review describes selective progesterone receptor modulators (SPRMs)—how they interact with the progesterone receptor to produce agonist/antagonist or mixed effects—and surveys their historical development and current clinical status, focusing on agents in use (mifepristone, ulipristal acetate) or halted in trials (asoprisnil due to endometrial changes; telapristone due to liver toxicity concerns). It highlights unmet needs in hormonally mediated gynecological disorders such as abnormal uterine bleeding (HMB), summarizing evidence on the role of ulipristal acetate (UPA) in emergency contraception (including its mechanism via LH surge inhibition/delay of ovulation, plus proposed endometrial effects) and its licensing for symptomatic uterine fibroids with rapid amenorrhoea and HMB control, while noting limitations such as questioned endometrial interpretations and dosing differences. The major caveat is that the paper is a narrative overview rather than a new empirical study, and it points to limited clinical translation for non-steroidal SPRMs. Relevance to endometriosis: adenomyosis and endometriosis are explicitly named among hormonally mediated gynecological problems that may be managed with SPRMs, although the remainder of the article focuses on SPRMs for HMB, contraception, and uterine fibroids rather than directly on endometriosis/endometriosis mechanisms or treatments.

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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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Upa

At the time of writing this review, we did not identify any RCTs evaluating the role of UPA in managing endometriosis and adenomyosis. Endometriosis is a condition in which there is the presence of endometrial glands and stroma outside the uterus. It affects one in ten of women of reproductive age and is associated with pelvic pain, HMB and infertility ( Eskenazi & Warner 1997 , Missmer & Cramer 2003 , Bedaiwy et al . 2009 ). There is conflicting and limited evidence regarding the role of UPA in endometriosis. In animal models (rats with surgically induced endometriosis), UPA was found to induce regression and atrophy of the endometriosis lesions. This was accompanied by upregulation of proapoptotic markers, reduced cell proliferation and inflammatory markers ( Huniadi et al . 2013 ). A case report by Bressler et al . described a significant reduction in endometriosis related refractory chronic pelvic pain, when treated with high dose UPA for 3 months ( Bressler et al . 2017 ). In contrast, Donnez et al . described excellent response to UPA treatment when administered for two 3-month courses with regards to reduction in fibroid size; however, no effect on an ovarian endometrioma, with both conditions co-existing in the same patient ( Donnez & Dolmans 2016 ). The current understanding is that endometriosis lesions occur as superficial endometriosis, deep infiltrating endometriosis (DIE) and ovarian endometriosis (endometriomas). The aetiopathogenesis of these subtypes is poorly understood and some authors consider them as distinct clinical and pathological entities. There is conflicting evidence on the response of endometriosis to UPA with no clear demarcation between the three subtypes, and therefore, further investigation in the form of well-designed RCTs is necessary. Bird et al . defined adenomyosis as ‘the benign invasion of the endometrium into the myometrium, producing a diffusely enlarged uterus which microscopically exhibits ectopic, non-neoplastic, endometrial glands and stroma surrounded by the hypertrophic and hyperplastic myometrium' ( Bird et al . 1972 ). The prevalence of adenomyosis is difficult to ascertain because of a wide variation in diagnostic criteria both with imaging modalities and with histology. It has been estimated that histological confirmation of adenomyosis ranges from 5 to 70% of patients who undergo hysterectomy ( Abbott 2017 ). With improvements in imaging technology, more cases of adenomyosis are now being diagnosed non-invasively both using 2D and 3D pelvic ultrasonography and MRI ( Bluhm & Dueholm 2019 , Liu et al . 2019 ). There is an emerging concept of ‘progesterone resistance’ in the pathogenesis of these hormone-dependent conditions. In a normal cycling human endometrium, levels of the progesterone receptor (PR-A, PR-B; 2 isoforms) increase under the influence of the oestrogen exposure in the follicular phase of the cycle and the levels of the oestrogen receptor (ER) also increase. After ovulation, the levels of ER decline under the influence of rising circulating progesterone concentrations. In women with endometriosis, reduced endometrial PR-A expression compared to eutopic endometrium and an absence of PR-B were reported ( Attia et al . 2000 ). This is likely a contributing mechanism, whereby progesterone does not trigger the expression of the endometrial steroid metabolising enzyme, 17 β hydroxysteroid dehydrogenase type 2 and subsequent metabolism of oestradiol (E2 - potent) to oestrone (E1 - less potent) ( Bulun 2009 , Bulun et al . 2010 , Reis et al . 2013 ). Conversion of potent E2 to less potent E1, which normally occurs in the secretory phase endometrium, is regarded as a critical protective mechanism against oestrogen-induced growth. Moreover, endometrial expression profiling has documented dysregulation of progesterone-responsive genes in women with endometriosis ( Taylor et al . 1999 , Aghajanova et al . 2010 ). Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. Women with PCOS present with diverse features which includes those involving the reproductive system, such as, irregular menstrual cycles, hirsutism, infertility and pregnancy complications, along with metabolic features (insulin resistance (IR), metabolic syndrome, prediabetes, type 2 diabetes (DM2) and cardiovascular risk factors ( Monash University 2018 ). Although the concept of altered response to endogenous progesterone (P4), ‘progesterone resistance’ has been addressed in the context of endometriosis, and it may be also evident in women with PCOS. A gene microanalysis by Savaris et al . reported that progesterone-regulated genes, including mitogen-inducible gene 6 (MIG6), leukemia inhibitory factor (LIF), GRB2-associated binding protein 1 (GAB1), S100P and claudin-4, were significantly lower in the endometrium of women with PCOS, whereas cell proliferation genes, such as Anillin and cyclin B1, were up-regulated. These data lend support to the concept of progesterone resistance ( Savaris et al . 2011 ). The altered expression of the isoforms of the progesterone receptor (PR-A, PR-B) and the downstream signalling pathways has also been proposed as a mechanism for progesterone resistance in women with PCOS; however, further discussion is beyond the scope of this review ( Li et al . 2014 ).

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

History

The search for drugs that modify progesterone activity with an aim to achieve contraception can be traced back to the 1960s ( Pincus 1960 ). The first SPRM, RU486 (mifepristone), was discovered in the 1980s, during the quest for discovery for anti-glucocorticoid drugs ( Moguilewsky & Philibert 1984 ). Several SPRMs have been developed ( Fig. 1 ) since, and the latest in this class of drugs is vilaprisan. The development of SPRMS is shown in the timeline in Fig. 1 . Figure 1 Key points in the of the development of SPRMs (timeline) and current clinical significance. Mifepristone and ulipristal acetate are the only SPRMs in current clinical use. The use of Asoprisnil was halted due to concerns regarding endometrial changes ( Guo & Groothuis 2018 , Lewis et al . 2018 ). Telapristone studies were halted due to liver toxicity concerns ( Lewis et al . 2018 ). Key points in the of the development of SPRMs (timeline) and current clinical significance. Mifepristone and ulipristal acetate are the only SPRMs in current clinical use. The use of Asoprisnil was halted due to concerns regarding endometrial changes ( Guo & Groothuis 2018 , Lewis et al . 2018 ). Telapristone studies were halted due to liver toxicity concerns ( Lewis et al . 2018 ). Non-steroidal SPRMS aim to achieve the effect of progesterone receptor binding that can selectively act as a progestin in the endometrium while acting as an antiprogestin within the leiomyoma; however, there is a limited clinical translation of these agents ( Catherino et al . 2010 ).

Clinical

The currently available information for vilaprisan is generated from human clinical phase I and II trials in women with HMB and fibroids ( Bradley et al . 2016 , Schütt et al . 2016 , 2018 , Schultze-Mosgau et al . 2017 , 2018 ). The results of the first trials comparing vilaprisan vs ulipristal acetate vs placebo in a randomised, double-blind, parallel-group fashion (ASTEROID 2 study) have not been published at the time of writing this paper. The findings from these trials are listed in Table 3 . Table 3 Summary of key findings of phase I and II clinical trials utilising vilaprisan. Phase I clinical trials (Schütt et al . 2016, 2018)  Vilaprisan 0.5–5 mg/day for 12 weeks   1. Maximal non-bleeding rates achieved at dose of 2 mg or higher per day.   2. Doses >0.5 mg/day are associated with a decrease in FSH and LH.   3. Follicular growth mid-follicular oestradiol levels maintained.   4. Ovulation inhibited on >80% of participants at doses ≥1 mg/day.   5. Return of menstruation in ≤52 days after discontinuation.   6. No serious adverse events. A non-dose dependent transient rise in liver transaminases seen during treatment with vilaprisan which returned to baseline.   7. PAEC present in 10% of women pre-treatment and with 100% frequency in women on 5 mg/day (dose dependant). At doses of 1 mg/day, PAEC was observed in 70–90% of women. Regression was noted in majority of women at first bleed post treatment with regression in all participants at 4–6 months. Phase II clinical trial (Bradley et al . 2016)  Vilaprisan 0.5–4 mg/day for 12 weeks   1. Amenorrhea (MBL <2 ml/28 days by alkali hematin) seen in 87–92% of participants at doses of 1 mg/day or higher.   2. Median time of amenorrhoea – 3 days.   3. Dose dependant reduction in fibroid size; up to 40% at 4 mg dose.   4. Improvements in HRQoL.   5. No serious adverse events.   6. PAEC seen in up to 40% of women on completing treatment with vilaprisan. Complete regression of PAEC to baseline levels was observed during the follow up period (24 weeks). Summary of key findings of phase I and II clinical trials utilising vilaprisan. Vilaprisan has been undergoing clinical trials for management of HMB with uterine fibroids (ASTEROID 5; NCT Identifier: 03240523, ASTEROID 6; NCT Identifier: 03194646 and ASTEROID 7; NCT Identifier: 03699176) and a phase 2B randomised placebo-controlled trial in managing women with symptomatic endometriosis (NCT Identifier: 03573336; VILLENDO Study). At the time of writing this article, all vilaprisan trials were on hold due to new safety findings in long-term toxicology study in rodents ( Bayer 2018 , Burger 2018 ).

Emergency

UPA is United States Food and Drug Administration (US FDA) approved as an emergency contraceptive and is licensed in the United Kingdom for this purpose, including for over the counter (OTC) use ( European Consortium for Emergency Contraception 2017 ). Evidence suggests that the most effective emergency contraceptive is a Copper intrauterine device (Cu-IUD). It has a failure rate of <1% when inserted within 5 days (120 h) after the first unprotected sexual intercourse (UPSI) in a natural cycle or within 5 days after the earliest estimated date of ovulation (whichever is later). The Faculty of Sexual and Reproductive Healthcare (FSRH) suggests it has the added advantage of providing ongoing contraception ( Cleland et al . 2012 , The Faculty of Sexual & Reproductive Healthcare 2017 ). There are limitations of using an IUD for this purpose; it cannot be used in women with an active pelvic infection, undiagnosed genital tract bleeding or distortion of uterine anatomy. It requires a medical professional available for insertion. Ongoing risks include that of uterine perforation, abnormal uterine bleeding and dysmenorrhoea in some users. Other emergency contraceptive methods licensed in the United Kingdom include oral levonorgestrel (LNG) and oral UPA. LNG is used in a dose of 1.5 mg orally (single dose) and is licensed for use up to 72 h after UPSI or contraceptive failure. UPA is used in a dose of 30 mg and is licensed for up to 120 h for the same indications ( The Faculty of Sexual & Reproductive Healthcare 2017 ). Current evidence suggests that UPA is more effective than LNG as an emergency contraceptive ( Glasier et al . 2010 , Shen et al . 2019 ). The combined hormonal ‘Yuzpe method’ is no longer recommended for use in the United Kingdom, as evidence suggests lower efficacy as compared to LNG EC alone ( Cheng et al . 2012 , Leung et al . 2016 ). The oestrogen–progestin regimen comprises two doses of a combination of 100 μg of ethinyl oestradiol and 0.5 mg of levonorgestrel each, the first dose taken within 72 h after intercourse and the second 12 h later ( Yuzpe & Lancee 1977 , Glasier 1997 ). There is a current lack of evidence to recommend the LNG-IUS as a method of emergency contraception ( The Faculty of Sexual & Reproductive Healthcare 2017 ).

Conclusion

SPRMs have been in development since the 1980s, and yet a perfect SPRM does not exist. The class of compounds do have some common effects, including suppression of the LH surge, anovulation, amenorrhoea and benign endometrial changes or PAEC. Some SPRMs have clear indications and therapeutic benefits, for example, mifepristone for pregnancy interruption and ulipristal acetate for emergency contraception and management of fibroid related HMB. There still appears to be a great void in what SPRMs could achieve in terms of their therapeutic potential. There are few well-conducted RCTs which examine the role of SPRMs in endometriosis, adenomyosis or hormonally mediated chronic pain syndromes. For AUB alone, which is common (affecting one in four women of reproductive age) and debilitating, the role of SPRMs yet remains to be determined. The UCON study (Ulipristal vs Coil for the Management of Heavy Menstrual Bleeding; EudraCT: 2014-003408-65) once completed may provide valuable insights as to the utility of SPRM (UPA) administration in women with and without fibroids. SPRMs may also offer the potential of long-term oestrogen free contraception with less unscheduled bleeding – the side effect occurring in 20% of users of progestin-only methods of contraception ( Lethaby et al . 2015 ). Optimal routes for administration for contraceptive indications will also require evaluation. The attractiveness of SPRMS lies in the fact that they may be orally administered but have the potential for local drug delivery, that is, via intrauterine or vaginal routes. They have the advantage of maintaining peripheral mid-follicular oestradiol levels, avoiding hypo-oestrogenic side effects. From the perspective of the clinician, this means a class of drugs which may help in the medical management of common gynaecological pathologies without the side-effect profile of current standard medical treatments. From the academic perspective, very little is known about the endometrial mechanisms underpinning the development of PAEC and the long-term implications on the endometrial molecular signature. These are reasons to further pursue research, development and undertake well-conducted clinical trials involving SPRMs with the ultimate goal of improving women’s health and their quality of life.

Ulipristal

UPA was first studied in the 1990s in the context of an ‘antifertility’ drug in keeping with the properties of RU486 (mifepristone), both in rats and humans ( Passaro et al . 1997 , Reel et al . 1998 ). Like mifepristone, UPA was labelled an ‘antiprogestin’ when initially developed and only in recent years has been classed as an SPRM. UPA is a steroidal SPRM with a structure of a 19 norprogesterone derivative: 17a–Acetoxy-11b-(4-N, N-Dimethylaminophenyl)-19-norpregna-4-9-diene-3,20 dione, also known as CDB 2914, since it was initially developed by the National Institute of Child Health and Human Development (NICHD). It is also known as HRP 2000 or VA 2914 ( Bouchard 2014 ). The chemical structure of UPA is illustrated in Fig. 2 . Figure 2 Chemical structure of UPA. Chemical structure of UPA.

Vilaprisan

Vilaprisan (BAY 1002670) is a more recent, potent, orally active SPRM. Vilaprisan was developed by and is the property of Bayer AG, Berlin, Germany. It is a 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)- dien-11-aryl derivative. Vilaprisan can weakly bind to the glucocorticoid receptor and androgen receptor with no effect on the oestrogen receptor ( Wagenfeld et al . 2013 , Möller et al . 2018 ). Its chemical structure is shown in Fig. 6 . Figure 6 Chemical structure of vilaprisan. Chemical structure of vilaprisan.

Declaration

H O D C has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (but with no personal remuneration) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc. and Myovant Sciences GmbH. H O D C receives royalties from UpToDate for the article on abnormal uterine bleeding. R R C has received support from Bayer AG as a clinical research fellow.

Introduction

Selective Progesterone Receptor Modulators (SPRMs) are a class of synthetic steroids with different molecular structures. They interact with the progesterone receptor (PR) and may exert an agonist, antagonist or a mixed response ( Lusher et al . 2011 ). Progesterone plays a vital role in the structure, function and regulation of the female reproductive tract, including pregnancy. Progesterone mediates its function by interacting with the PR, a member of a superfamily of almost 50 ligand-activated nuclear transcription factors ( McEwan 2009 ). A large number of gynaecological problems such as abnormal uterine bleeding (AUB), fibroids (leiomyoma), adenomyosis, endometriosis and reproductive tract cancers are hormonally mediated; therefore, SPRMs hold great potential for the management of women with gynaecological disorders.

Mifepristone

Although a full review of the non-gynaecological benefits of mifepristone is beyond the scope of this article, it has been explored and used in the clinical context for the indications discussed in the subsequent section. Mifepristone has been explored as an anti-glucocorticoid drug. This may particularly be of value in the medical treatment of Cushing’s disease; mifepristone is considered as an adjuvant drug in this regard ( Carmichael & Fleseriu 2013 ). The drug also shows potential for treating neuropsychiatric disorders, mood disorders and Alzheimer’s disease ( DeBattista & Belanoff 2006 ). Mifepristone has also been trialled in the management of inoperable meningiomas ( Haak et al . 1990 , Matsuda et al . 1994 ). For its antiprogesterone properties, mifepristone has been evaluated in the management of breast cancers ( Romieu et al . 1987 , Klijn et al . 1989 ). Treatment with RU486 (mifepristone) has been shown to prevent mammary tumorigenesis in Brca1 / Trp53 -deficient mice ( Poole et al . 2006 ). The potential role of SPRMs in the prevention of breast cancer has been previously proposed ( Bouchard et al . 2011 ).

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