Selective progesterone receptor modulators 2: use in reproductive medicine

Review

10.1517/14656560802335283 © 2008 Informa UK Ltd ISSN 1465-6566 2473All rights reserved: reproduction in whole or in part not permitted

Selective progesterone receptor modulators 2: use in reproductive medicine Giuseppe Benagiano , Carlo Bastianelli & Manuela Farris † † University ‘la Sapienza’, Department of Gynaecology and Obstetrics, Policlinico Umberto I ° , Viale Regina Margherita 245, 00161 Roma, Italy

Background : Synthetic compounds can bind to progesterone receptors and these progesterone receptor ligands exhibit a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. These substances have been classified as antiprogestins or as selective progesterone receptor modulators. Objective : There are several hundred selective progesterone receptor modulators available, although only a dozen or so have been evaluated to any significant extent. The best-known selective progesterone receptor modulators are mifepristone (RU 486), asoprisnil (J 867), onapristone (ZK 98299), ulipristal (CDB 2914), Proellex ™ (CDB 4124), ORG 33628 and ORG 31710. Methods : A careful evaluation of existing major review papers and of recently published articles was carried out for the indications under review, focusing not only on mifepristone, but also on those other selective progesterone receptor modulators for which data are available. Results/conclusions : Outside pregnancy, selective progesterone receptor modulators are used or have been tested clinically for a number of indications in reproductive medicine: as oral contraceptives, alone or in combination with a progestin, to improve cycle control in users of progestin-only contraceptives, as emergency contraceptives, for the medical treatment of uterine fibroids, in cases of endometriosis and premenstrual syndrome and to improve ovarian stimulation prior to in vitro fertilisation. In the authors’ opinion, as of today, few applications outside pregnancy seem worthy of large-scale use: emergency contraception and long-term medical management of uterine fibroids and possibly of endometriosis.

Keywords: antiprogestins , contraception , emergency contraception , endometriosis , in vitro fertilisation , selective progesterone receptor modulators , uterine leiomyomata

Expert Opin. Pharmacother. (2008) 9(14):2473-2485

1. Introduction

In a preceding paper the authors summarised established and possible applications of selective progesterone receptor modulators (SPRMs) during pregnancy and at delivery [1] . This new class of compounds, initially named antiprogestins, was accidentally discovered when chemists in search of glucocorticoid antagonists synthesised a number of 11 β -phenyl-substituted steroids [2,3] : for this reason they all possess both antiprogestin and antiglucocorticoid activity. Of the several hundred compounds with antiprogestational activity synthesised to date only a dozen or so have been evaluated to any significant extent [4,5] . The following have reached the stage of human application: mifepristone (RU 486), asoprisnil (J 867) onapristone (ZK 98299), ulipristal (CDB 2914), Proellex ™ (CDB 4124), ORG 33628 and ORG 31710. Their characteristics have been summarised elsewhere [1]

1. Introduction

2. Fertility regulation

3. Gynaecology

4. Conclusions

5. Expert opinion

Selective progesterone receptor modulators 2: use in reproductive medicine

2474 Expert Opin. Pharmacother. (2008) 9(14)

Here the authors wish to discuss the clinical applications of SPRMs in reproductive medicine. The reader can also consult several other reviews [2-19] .

2. Fertility regulation

2.1 Contraception Hormonal contraception can be administered today in a variety of ways, although by far the most common modality is the oral route (cf. [20] ). All presently available hormonal contraceptives use a progestin and this fact prompted efforts aimed at determining whether an antiprogestin could, alone, replace an oral contraceptive. The first and best-investigated compound for this purpose is mifepristone. Von Hertzen and Van Look [21] provided a comprehensive review of the available options for contraceptive applications of mifepristone.

2.1.1 Mifepristone The potential contraceptive effect of RU 486 was mentioned in the very first publication on its abortifacient properties [22] In addition, it has been known for some time that mife-pristone at doses of 2 and 5 mg/day has contraceptive properties: for instance, at a dose of 5 mg/day RU 486 inhibits ovulation by suppressing the luteinising hormone (LH) surge and it induces amenorrhoea in the majority of women [23,24] . In contradistinction to this, antiprogestins have no effect on male fertility and even very high doses do not disturb spermatogenesis or sperm function [21] .

The first clinical use of mifepristone as a contraceptive was published in 1993, using a monthly dose of 200 mg of mifepristone administered 2 days after the LH surge [25] . The study concluded that the effect of mifepristone on the endometrium was sufficient to prevent pregnancy. Many other clinical trials followed, but 15 years later no large-scale development of RU 486 as a contraceptive has been tried.

2.1.1.1 Daily administration Several groups have pursued the development of an oral contraceptive based on the administration of mifepristone with unsatisfactory results: the low-dose regimens tested either caused bleeding irregularities, did not block ovulation or altered the amount of menstrual bleeding, whereas higher doses caused not only anovulation but also amenorrhoea [21] . Daily administration of RU 486 produces significant changes in endometrial biochemistry, although these modifications are not sufficient to prevent pregnancy [26,27] .

The contraceptive potential of 2 and 5 mg of mifepristone has recently been evaluated in a double-blind fashion: in this trial, the majority of treated women became amenorrhoeic. Although no pregnancy occurred over 200 months of exposure, several factors induce caution in interpreting the results [27] : for this reason these findings need to be confirmed in larger studies.

Another small trial compared the effects of mifepristone at 5 mg/day and those of a progestin-only ‘mini-pill’

containing levonorgestrel (LNG) at 30 µg [28] and significant differences in bleeding patterns were found between the two groups: almost 50% of the women taking mifepristone were amenorrhoeic while none of those taking LNG reported an absence of bleeding. Only three women in the RU 486 group bled or spotted, whereas in the LNG group the majority (61%) had a number of bleeding days in the range of normal menstruation. Ovulation occurred in 19% of women taking mifepristone and 30% of those taking LNG. Over 356 months of observation no pregnancy occurred in women taking mifepristone: strangely enough, in women using both mifepristone and a condom for dual protection, two pregnancies ensued. Almost 50% of women in the mifepristone group showed cystic glandular dilatation of the endometrium, although in no case did it progress to hyperplasia or atypia. This phenomenon has been observed in other trials and underlines the different action of this SPRM on different target structures.

2.1.1.2 Weekly regimen It has been suggested that women in some cultural settings may prefer not to have to take a daily pill and, for this reason, different doses of mifepristone have been tested as a weekly contraceptive: 2.5, 5, 10, 25 and 50 mg. Mifepristone did not inhibit ovulation at any dosage tested with ensuing high failure rates [29-31] . At the same time, as expected, mifepristone caused a desynchronisation of endometrial development. Small clinical trials have confirmed that a lack of inhibition of ovulation is accompanied by high failure [21] . As a consequence, this administration schedule has not been pursued.

2.1.1.3 Sequential antiprogestin–progestin use Back in 1990 Kekkonen et al. [32] showed that, when a daily dose of 25 mg of mifepristone was administered for 14 days followed by 10 days of 5 mg of norethisterone, ovulation could be suppressed during mifepristone administration, while it occurred during norethisterone treatment. Further studies that investigated different doses of mifepristone followed by a progestin confirmed these findings [33,34] .

Ovulation inhibition seems to depend on several factors, for example the duration and dose of mifepristone, the characteristics of the progestin used and the sensitivity of women to the treatment. If ovulation occurred it happened during the progestin treatment [34] .

On the basis of these results Croxatto et al. [35] tested a sequential regimen with mifepristone at 10 mg for 15 days followed by 10 mg of medroxyprogesterone acetate for 13 days in a small study of 1-year’s duration using a continuous administration regimen. They found that ovulation was suppressed in 90% of the cycles with important changes in the cervical mucus scores even when ovulation occurred. In spite of this, one pregnancy occurred over 359 woman months of exposure.

Benagiano, Bastianelli & Farris

Expert Opin. Pharmacother. (2008) 9(14) 2475

Given these results, it seems unlikely that at least mifepristone will ever become an effective and acceptable oral contraceptive, with or without a progestin.

2.1.1.4 Adjuvant regimens It is important to mention that RU 486 has been used as an ‘adjuvant’ in women treated with long-acting progestin-only methods. First, two separate studies have shown that it decreases the incidence of breakthrough bleeding in women using Norplant ™ , a levonorgestrel-releasing subdermal implant (cf. [36] ). In the first trial [37] , 100 mg of mifepristone was administered twice monthly during 5 months: although the women experienced the same number of bleeding episodes during treatment as the controls, the duration of bleeding was significantly less prolonged. In the second trial [38] , 50 mg of mifepristone was given once every 4 weeks to women using Norplant and complaining of irregular bleeding. Treated women experienced significantly shorter bleeding episodes than controls and they were more likely to find treatment acceptable.

Given this partial success, RU 486 has also been tested in connection with depo-medroxyprogesterone acetate (DMPA), a long-acting injectable progestin-only contraceptive that, although very effective, is marred by a high incidence of breakthrough bleeding, often leading to discontinuation (cf. [39] ). The effect of mifepristone in regularising bleeding patterns was tested in a clinical trial involving 20 regularly cycling women receiving DMPA for the first time. The authors concluded that 50 mg of mifepristone taken every 2 weeks was indeed able to decrease the incidence of breakthrough bleeding and that this effect may have been due to modulation of endometrial oestrogen and progesterone receptors, since immunostaining for oestrogen receptors increased, whereas that for progesterone receptors fell following treatment with the antiprogestin [40] . In order to study the mechanism of this positive action, serial biopsies were obtained from women treated with DMPA and RU 486. Endometrial matrix metalloproteinases 1 and 9 and CD3-positive and mast tryptase-positive cells increased following injection of DMPA, whereas the addition of mifepristone to DMPA-exposed endometrial tissue for 1 week significantly decreased stromal matrix metalloproteinase 9 expression and the number of CD3-positive and mast tryptase-positive cells [41] .

Recently, the molecular action of RU 486 on the endometrium of DMPA-treated women has been investigated in-depth: a first study showed that the administration of DMPA led to a substantial inhibition of endometrial secretory leukocyte protease inhibitor protein and mRNA and that the addition of RU 486 partially restored the expression of glandular secretory leukocyte protease inhibitor [42] , whereas a second investigation showed that, in users of DMPA, the expression of endometrial oestrogen receptor subtypes alpha and beta, progesterone receptors A and B and androgen receptor messenger RNA and protein

increased significantly after 1 week of mifepristone, although this increase was no longer measurable after 10 weeks. This suggests that, whereas short-term exposure of RU 486 promotes cell proliferation, continuous treatment no longer suppresses the expression of these receptors and therefore the endometrium remains atropic [43] .

Notwithstanding the data reported above, a recent Cochrane review [44] evaluating various preventive and therapeutic approaches for normalising bleeding irregularities associated with the use of progestin-only contraceptives did not mention mifepristone. The review concluded that oestrogen treatment reduces the number of days of an ongoing bleeding episode in DMPA and Norplant users. However, treatment frequently led to discontinuation due to gastrointestinal upset. The combination of oral ethinyl oestradiol and levonorgestrel also seemed to improve bleeding patterns in Norplant users, although the discontinuation rates remained unchanged.

Finally, a variety of non-steroidal anti-inflammatory drugs were evaluated for their ability in treating abnormal bleeding, with mixed results.

2.1.2 Ulipristal (CDB 2914) Recently, the Population Council received a grant from the US National Institutes of Health (NIH) for the development of a contraceptive vaginal ring releasing ulipristal (CDB 2914): unpublished dose-finding studies defined the ovulation suppression dose and the pharmaco-kinetic profile for the ring (R Sitruk-Ware, personal communication). The only published mention of this modality is in a table in a paper by Sitruk-Ware [45] .

As already stated, the biological effects of CDB 2914 vary according to the time in the menstrual cycle when the compound is administered. Given in the mid-follicular phase CDB 2914 (50 mg) inhibits follicular development and delays ovulation and menses. At 100 mg, in some cases the original follicle ceases to develop and a new follicle is recruited. Given at the mid-luteal phase, on the other hand, there is a dose-dependent effect on the length of the cycle, which is, on average, lengthened by ∼ 1 – 2 days [11] .

2.1.3 ORG 31710 and ORG 33628 These compounds seem effective when used in the contraceptive modality referred to as ‘menstrual regulation’, since, in non-human primates, they induce vaginal bleeding after single-dose administration during the luteal phase of a normal cycle [46] . Given this property, the two SPRMs have been tested with the aim of improving cycle control in women using the progestin-only mini-pill Cerazette ® (which contains 75 mg of desogestrel administered daily and without interruption) (cf. [47] ). Not only did ORG 31710 induce monthly bleeding, it also substantially reduced breakthrough bleeding. Unfortunately, in contradiction to what happens in monkeys, in women this positive effect is limited to < 2 weeks. Similar results have been obtained



using ORG 33628: here again, the improvement in the bleeding patterns of Cerazette ® users was not considered effective enough [48,49] .

Researchers at Organon then tried continuous combined daily treatment of the same mini-pill and ORG 33628. The underlying rationale was that the progestin would block ovulation, whereas the SPRM would effectively prevent breakthrough bleeding. Three different dosages of ORG 33628 were tested: whereas vaginal bleeding was inversely proportional to the SPRM dose, the rate of inhibition of ovulation decreased with increasing doses [50] .

2.1.4 Onapristone Preliminary studies conducted in non-human primates have shown that this antiprogestin can produce a satisfactory contraceptive effect when given daily throughout the menstrual cycle: in the majority of animals the mean menstrual cycle length was not altered significantly and the majority of cycles were ovulatory [51] . Further animal investigations [52] have indicated that there is dose-dependent endometrial atrophy, whereas ultrastructural analysis showed dose-dependent degenerative changes in subcellular structures. These studies showed that modulation of endometrial receptivity is a promising new approach in developing new fertility-regulating agents, since it allows a contraceptive effect specifically targeted at the endometrium. In preliminary studies using non-human primates, onapristone, which is considered a ‘pure’ antiprogestin, seemed particularly promising. When given at three different dosages for 7 days in the early follicular phase, the two higher doses (15 or 50 mg/day) were sufficient for arresting follicular growth and the rise in circulating oestradiol and delaying the gonadotropin surge: however, after discontinuation of treatment the leading follicle resumed its growth, ovulation occurred and the luteal phase was not significantly modified [53] .

The contraceptive potential of another antiprogestin of the same family (ZK 230211) was recently tested. The antiprogestin was incorporated into an intrauterine system and tested against the classic levonorgestrel-releasing device (the levonorgestrel intrauterine system). Histological evaluation showed that ZK 230211 was measurable in all endometrial specimens and that the endometrium was partly suppressed in less than one-third of subjects: this was compared with two-thirds of the women fitted with the levonorgestrel intrauterine system. Days of bleeding and spotting were unchanged by the use of ZK intrauterine systems but were increased by levonorgestrel. This pilot study concluded that intrauterine release of ZK 230211 did not change, at least in the short-term, bleeding patterns or result in endometrial suppression [54] .

2.2 Emergency contraception The presently accepted definition of ‘emergency contraception’ includes all ‘those contraceptive methods that provide a woman with a safe means of preventing an unwanted

pregnancy following unprotected sexual intercourse, or in the event of potential contraceptive failure’ [55] . This definition is not ubiquitously accepted, as it is based on the World Health Organisation’s [56] (WHO) terminology, namely that gestation begins at implantation, a concept rejected by those who hold that a new human being exists from syngamy, once fertilisation has taken place.

Irrespective of the ethical paradigm followed, emergency contraception is now widely available and uses hormones, antihormones and intrauterine devices (cf. [57] ). Several SPRMs have been tested as emergency contraceptives, although by far the most thoroughly tested is mifepristone.

2.2.1 Mifepristone Whereas the use of mifepristone as a ‘classic contraceptive’ (i.e., to prevent ovulation and/or fertilisation) may end up as problematic, this compound has been shown to be highly effective as an ‘antiprogestin-based emergency hormonal contraceptive’.

The WHO Special Programme of Research in Human Reproduction has contributed in a substantial way to the development of RU 486 as an emergency contraceptive [58-60] . In a series of preliminary trials, dosages ranging from 50 to 600 mg have been tested, all with promising results. A further trial conducted by the WHO documented that a dose of 10 mg had the same effectiveness (1.2% failure rate) as all the higher dosages in preventing the establishment of pregnancy when administered up to 120 h after unprotected intercourse. It also showed that the effectiveness of a single dose of 10 mg of mifepristone was no different from that observed with the two already available levonorgestrel regimens [61] .

2.2.1.1 Use effectiveness When taken together, data collected by the WHO have indicated that RU 486 is highly effective at a dose of 10 mg taken within 5 days of unprotected intercourse and that this dosage has the same effectiveness (1.2% failure rate) as the much higher doses initially employed. Thus, it is thanks to the WHO that the effective regimen has been determined as a single dose of 10 mg of mifepristone and that proof was obtained that this regimen is more effective than oestrogen–progestin combinations or progestin-only pills [62] . A recently published Cochrane review [63] has now concluded that doses of mifepristone of between 25 and 50 mg are superior to other hormonal regimens. In addition, low doses of mifepristone (< 25 mg) are probably more effective than levonorgestrel at 0.75 mg (two doses), although no conclusive evidence exists. Today RU 486 is available in China at doses of 10 and 25 mg.

2.2.1.2 Mechanism of action The effects of mifepristone on the human menstrual cycle depend on the stage of the cycle at which it is administered. During the mid- to late follicular phase RU 486 blocks



further growth of the dominant follicle and counteracts the positive feedback of oestradiol, thereby preventing the mid-cycle LH surge and delaying ovulation [10] .

In contradiction to what seems to be the case in the majority of women using progestin-only emergency contraception, when administered at or immediately after ovulation RU 486 seems to act by blocking tubal transport and/or nidation. Indeed, the most recent data tend to document that, in contradiction to SPRMs, combined oral contraceptives and progestin-only pill preparations can hardly be effective after fertilisation has occurred and therefore act mostly as ‘true’ contraceptives [64] . This has been documented in an in vitro three-dimensional endometrial model in which early luteal phase human endometrial stromal and epithelial cells were co-cultured and expressed the factors involved in endometrial receptivity. Fifteen embryos were cultured with mifepristone and none attached to the endometrial construct, whereas 10 out of 17 in the control group and six out of 14 in the levonorgestrel group did attached. This seems to demonstrate that RU 486 inhibits blastocyst attachment, whereas levonorgestrel does not [65] .

2.2.1.3 Adverse events The specific mechanism of action of RU 486 is responsible for the high incidence rate of cycle disturbances observed (in 9 – 18% of all women there is more than a 5-day delay of menses).

Other side effects, such as nausea and vomiting, are less likely with mifepristone than with the classic Yuzpe regimen, based on the administration of a combined oral contraceptive [62] .

2.2.1.4 Indications and contraindications With the exception of China the drug is not on the market, and - for this reason - indications and contraindications have not yet been specified. The latest edition of the WHO eligibility criteria does not list this method.

2.2.2 Ulipristal Early clinical experience in applying this SPRM to emergency contraception was obtained by the US NIH and by the licensee. The NIH conducted two studies. The first compared the efficacy of 50 mg of non-micronised CDB 2914 versus levonorgestrel at 1.5 mg (two doses of 0.75 mg). In the second study 10 mg of CDB 2914 in micronised form was compared to 50 mg of non-micronised compound. There was no statistical difference, albeit the higher dose was somewhat better. The licensee also conducted two studies, one in the US and the other in the UK. In both the dose was 30 mg of micronised CDB 2914, but in the second study the time period from unprotected intercourse was extended up to 120 h [66] . The licensee hopes to submit the full dossier to the US FDA this year.

2.2.3 Onapristone Some 10 years ago an international trial evaluated the effect of mifepristone and onapristone on the endometrium. The

study documented that treatment with the two SPRMs was capable of retarding the development of secretory changes in the endometrium without affecting the length of the luteal phase. Measuring a variety of receptivity parameters the trial concluded that the administration of these agents adversely affected implantation. When studying healthy volunteers with regular menstrual cycles, it was determined that treatment with either antiprogestin did not affect the length of the luteal phase between cycles or the follicular phase. After treatment endometrial maturation was retarded and secretory changes were impaired [67] .

3. Gynaecology

3.1 Uterine leiomyomata For over 100 years the treatment of uterine leiomyomata was exclusively surgical: it was only during the second part of the twentieth century that a variety of medical regimens based on scientific criteria were proposed (cf. [12] ).

Most of them were originally developed as alternatives to surgery, although clinical use showed they were better suited for adjuvant therapy before or after surgery. Nonetheless, a number of non-surgical modalities are used today for the treatment of uterine fibroids, but none has been shown to be of value in the patient desiring future fertility, for whom myomectomy remains the standard of care, although recently promising results have been obtained with uterine artery embolisation [68] . Today medical therapy has gained acceptance to the point that several national guidelines mention some of these modalities for being routinely employed [69,70] .

Besides guidelines issued by government agencies, several review papers have also been published summarising present knowledge on the variety of medical modalities available for the treatment of uterine leiomyomata [71-76] .

In spite of renewed interest and a number of advances in the pathogenesis and treatment of fibroids, a systematic review of the literature on the surgical and non-surgical management of uterine leiomyomata conducted a few years ago by Myers et al. [77] led to the conclusion that ‘the available evidence on the management of uterine leiomyomata is of poor quality. Patients, clinicians, and policymakers do not have the data needed to make informed decisions about appropriate treatment’.

3.1.1 Rationale Over the last two decades the pathogenesis of leiomyomata has been extensively investigated and a number of factors conditioning their presence have been identified. For instance, it is today well known that leiomyoma cells present a number of chromosomal aberrations and that this phenomenon may be the consequence of the presence of specific genes. In addition, several studies have shown that each leiomyoma has a monoclonal origin. For instance, a study just published demonstrated monoclonality in all of



the 315 nodules recovered from 76 cases. Seven nodules from a multinodular case with a morphology indicative of mitotically active leiomyomata were shown to carry an identical inactivated allele, indicating a unicellular origin and malignant nature [78] .

Irrespective of their origin, fibroids’ development is highly dependent on ovarian steroid hormones and for many years the classic assumption has been that oestrogens are responsible for leiomyomata’s growth, since these tumours are exceptional before puberty and regress after the menopause (cf. [79] ). In contradiction to this, it was assumed that progesterone exerts a beneficial effect on fibroid growth, since during pregnancy they often remain unchanged and those that do grow usually do so during the first 4 – 5 months only: thereafter they may regress and even undergo so-called red degeneration [80] . In addition, they tend to regress following progestin treatment [81] and high-dose progestins can slow down fibroid regrowth following discontinuation of gonadotropin releasing hormone analogue (GnRHA) therapy [82] .

This simple paradigm must now be basically reviewed [83] , as extensively discussed by Spitz and Chwalisz [13] , Spitz [14] and Spitz et al. [15] . First, several studies have indicated that the addition of a progestin at the beginning of GnRHA treatment prevents fibroid shrinkage [84,85] . Specifically, Carr et al. [86] prospectively compared the effectiveness of administering medroxyprogesterone acetate in either the first or last 12-week period along with a 6-month course of the GnRHA leuprolide acetate and at 12 weeks observed a total uterine volume decrease to 73% of the baseline in patients treated with placebo during this period. However, the volume did not change in those given medroxyprogesterone acetate immediately. Second, it has been established that there is a higher mitotic index in leiomyomata obtained during the secretory phase of the cycle when compared with the proliferative one [87] . Third, it has been discovered that a number of other players have a role in myoma growth: these include, among others, epidermal growth factor (EGF), insulin-like growth factors (IGF) I and II and growth hormone. Fourth, it has been proven that, at physiological doses, progesterone is a stimulant of growth factor expression. Finally, recent data have shown an elevation of EGF mRNA in fibroids compared with normal myometrium, but only when specimens are obtained during the luteal phase.

On the basis of present knowledge, it is more than reasonable to attempt medical management of uterine fibroids using SPRMs, since they may be acting as non-competitive anti-oestrogens. On the one hand, they are able to antagonise the mitogenic effect of oestrogens on the endometrium, as shown in ovariectomised monkeys, while on the other they produce chronic anovulation, possibly by interfering with the hypothalamic–pituitary–ovarian axis.

Chinese scientists [88,89] have investigated the possible mechanisms through which SPRMs may act on fibroids. Starting from observation of an overexpression of progesterone receptor mRNA and progesterone receptor protein in

leiomyomata, they speculated that one of the mechanisms of mifepristone’s action in decreasing a leiomyoma’s volume might be related to suppression of the expression of the progesterone receptor gene. Interestingly enough, untreated leiomyomata had significantly greater amounts of EGF mRNA than adjacent normal myometrium only in the luteal phase of cycle. Similarly, leiomyomata untreated with mifepristone also had significantly larger amounts of progesterone receptors. These findings suggest that the luteal increase of EGF mRNA is mainly controlled by progesterone and that RU 486 inhibits EGF gene expression in leiomyomata. This observation suggests that progesterone not oestradiol is a stimulant of growth factor expression in myometrium.

3.1.2 Clinical use Both asoprisnil and mifepristone have been used in the medical treatment of uterine leiomyomata.

3.1.2.1 Mifepristone The pharmacodynamic effects of mifepristone indicate that this antiprogestin represents a very promising option for the medical treatment of fibroids. Shrinkage can be obtained even at low doses without causing severe hypo-oestrogenism, which means that therapy can be prolonged, at least in theory, for long periods, thus representing a real alternative to surgery.

Alvarez-Murphy et al. [90] were the first to attempt to reduce leiomyomata volumes with RU 486 at a daily dose of 50 mg in 10 patients over a 3-month period. The antiprogestin’s administration resulted in a significant decline in the volume of the majority of measurable masses, which was in the order of 50% at 12 weeks. It is noteworthy that individual responses varied from 0 to 87%, once more underlining the complexity of the issue. There was a significant decrease in the progesterone receptor staining, whereas no significant variation in the oestrogen receptor content was observed in leiomyomata and in the myometrium of mifepristone-treated subjects compared to controls.

In the 1990s Yen [91] conducted the first trial with doses as low as 5 mg of mifepristone. Using 25 mg daily, the results were as good as those obtained with 50 mg, whereas with 5 mg the time-dependent progressive regression was no longer apparent. On the basis of these results, Yen [90] foresaw a therapeutic ‘step-down’ strategy based on daily administration of 25 mg for the first 3 months, followed by a maintenance regimen of 5 mg daily.

For a period of time little new evidence appeared and in 2004 Steinauer et al. [92] carried out a computerised search of information published from 1995 to 2002 and identified six before-and-after clinical trials involving a total of 166 women with symptomatic uterine leiomyomata. The subjects received 5 – 50 mg/day of RU 486 for 3 – 6 months. Daily treatment with all doses of mifepristone resulted in reductions in uterine and leiomyoma volumes ranging from



27 to 49% and 26 to 74%, respectively. In addition, treatment reduced the prevalence and severity of dysmenorrhoea, menorrhagia and pelvic pressure, with amenorrhoea being present in a majority of patients (63 – 100%). As reported in other studies, a notable side effect was endometrial hyperplasia, which was evidenced in 28% of the women in whom a biopsy was performed.

An additional randomised placebo-controlled study has been published since, involving 42 women with symptomatic leiomyomata and uterine volumes of 160 ml or more who were given mifepristone at 5 mg daily or placebo for 26 weeks. Women randomised to mifepristone showed an improvement in their quality of life in connection with previous myoma-specific symptomatology. Uterine size was reduced by 47%: 41% became amenorrhoeic and anaemia, when present, improved. Compared with the placebo group, the improvements in these outcomes in the treatment group were significantly greater. No endometrial hyperplasia was noted in any participant in this trial [93] .

In conclusion, it is today well established that low-dose mifepristone improves leiomyoma-specific quality of life and reduces leiomyoma size among women with symptomatic fibroids. Interestingly, the effect of RU 486 is accompanied by a reduction in uterine blood flow. In a comparative study, both RU 486 and leuprolide acetate were effective in decreasing blood flow to the uterus (increasing the resistance index) and decreasing uterine volumes at 3 months [94] . This phenomenon suggests that progesterone plays an important role in the regulation of uterine perfusion and may point to the mechanism for the decrease in uterine size and uterine blood loss at the time of surgery. In addition, it provides a rationale for treating fibroids through uterine artery embolisation.

3.1.2.2 Asoprisnil Morikawa et al. [95] showed that asoprisnil may reduce collagen deposition in cultured leiomyoma cells through decreasing collagen synthesis, although no comparable effect is seen on cultured normal myometrial cells.

These findings offer a good a posteriori rationale for earlier work indicating that the use of asoprisnil represents a promising new medical treatment for uterine fibroids due to its partial agonist activity. These early clinical studies showed that J 867 induces amenorrhoea and a reduction in fibroid volumes in a dose-dependent manner [17] . A first multicentre double-blind placebo-controlled study of asoprisnil (5, 10 and 25 mg) was conducted in the 1990s [76] . In this study, the antiprogestin significantly suppressed both the duration and intensity of uterine bleeding, without inducing irregular bleeding: in addition, it increased the haemoglobin concentration and caused a dose-dependent amenorrhoea during the entire treatment period. Finally, J 867 reduced total uterine volumes and the volume of the largest leiomyoma in a dose-dependent manner [17] .

3.1.2.3 Ulipristal A recent investigation suggested that progesterone has dual actions on leiomyoma growth [18] : one is to stimulate the growth through upregulating EGF and Bcl-2 expression and the other is to inhibit the growth through downregulating IGF-I expression in the cells. The study also found that ulipristal inhibits proliferation and stimulates apoptosis of leiomyoma cells without affecting normal myometrial cells. This SPRM can also inhibit vascular EGF and adrenomedullin expression in leiomyoma cells, but not in normal myometrial cells. This cell type-specific action of CDB 2914 shows potential usefulness in the medical treatment of uterine myomas.

This has now been proven in a study just published [96] in which 22 premenopausal women with symptomatic uterine leiomyomata were randomly assigned to treatment with ulipristal at two different doses (10 or 20 mg) or to placebo for 3 months. Leiomyoma volumes were significantly reduced in those patients to whom CDB 2914 had been administered (36 and 21% in the 10- and 20-mg groups, respectively). During treatment, haemoglobin was unchanged and the median oestradiol level was > 50 pg/ml in all groups. In addition, ulipristal eliminated menstrual bleeding and inhibited ovulation. Finally, it improved the concern scores of the uterine leiomyoma symptom quality of life subscale.

3.1.2.4 Sequential use of mifepristone Taking advantage of the unique features of RU 486 and of the fact that its low-dose administration allows oestrogen levels comparable to those observed in the early follicular phase, the use of mifepristone has been proposed in order to avoid surgery altogether. The suggested regimen would use the SPRM in a sequential fashion after obtaining a proper volume reduction with a GnRHA, either a superagonist or an antagonist. In particular, in the presence of severe metro-rrhagia, after a 3 – 4-month administration of an analogue, when full shrinkage of the fibroids is obtained, long-term treatment with low-dose mifepristone could be instituted and continued until menopause [16] . The main advantage of this long-term regimen would be the preservation of mid-follicular oestrogen levels, thus avoiding the negative long-term effects of hypo-oestrogenism. A word of caution is necessary in view of the possibility of endometrial hyperplasia in these patients.

3.2 Endometriosis It is well known that endometriotic implants contain both oestrogen and progesterone receptors localised in the glandular epithelium and in the stroma [97] . Although the receptor content in the heterotopic endometrium is more heterogeneous and, in response to endogenous hormones, does not undergo cyclic changes throughout the menstrual cycle, various medical treatments (danazol, medroxyprogesterone acetate and combined oral contraceptives) produce a

https://www.researchgate.net/publication/14996685_The_effects_of_RU_486_and_leuprolide_acetate_on_uterine_artery_blood_flow_in_the_fibroid_uterus_A_prospective_randomized_study?el=1_x_8&enrichId=rgreq-37a7f0b39913324f8d95ba8e043a2f89-XXX&enrichSource=Y292ZXJQYWdlOzIzMjQ0MDM5O0FTOjEyMDIzMDc0MzM4NDA2NUAxNDA1Njc2NjUxNzk2

https://www.researchgate.net/publication/302058463_Immunohistochemical_analysis_of_estrogen_and_progesterone_receptors_in_endometriosis_comparison_with_normal_endometrium_during_the_menstrual_cycle_and_the_effect_of_medical_therapySupported_by_Nationa?el=1_x_8&enrichId=rgreq-37a7f0b39913324f8d95ba8e043a2f89-XXX&enrichSource=Y292ZXJQYWdlOzIzMjQ0MDM5O0FTOjEyMDIzMDc0MzM4NDA2NUAxNDA1Njc2NjUxNzk2



substantial decrease in both the oestrogen and progesterone receptor content.

To test the hypothesis that the action of SPRMs may result in inactivation of the endometriotic implant, Wolf et al. [98] used castrated monkeys pretreated with oestradiol for evaluating the effect of mifepristone on the eutopic endometrium and found that pretreatment produced a thick endometrium with a dense stroma and tubular glands. The addition of progesterone induced secretory transformations and, if mifepristone was administered in these primed animals together with progesterone, the transformation of the endometrium was inhibited: the endometrial thickness was reduced, the majority of the glands remained tubular, with a pseudostratified epithelium and there was no evidence of secretory activity.

According to Chwalisz et al. [15,99] the major goal of medical treatment of endometriosis is to create an acyclic hypo-oestrogenic environment either by blocking ovarian oestrogen secretion or by locally inhibiting oestrogenic stimulation of the ectopic endometrium. Chwalisz et al. [15,99] mentioned three reasons why SPRMs seem particularly promising: they afford selective inhibition of endometrial proliferation without systemic effects of oestrogen deprivation, they cause reversible suppression of endometrial bleeding and they can suppress endometrial prostaglandin production in a tissue-specific manner.

The first report ever published on the improvement of pelvic pain in patients with pelvic endometriosis is that of Kettel et al. [100] who gave a daily dose of 100 mg of anti-progestin during 3 months to six normally cycling women: in addition to pain relief, two women successfully conceived after completion of treatment, while relief of symptoms persisted in three patients for more than 1 year and pain only recurred in the last subject. The same group then published three additional reports confirming that doses of RU 486 between 5 and 50 mg were able to produce an improvement in the symptomatology, as well as in the physical appearance of the implants [101-103] . More recently, Chwalisz et al. [15] mentioned two randomised placebo-controlled dose-finding Phase II studies with asoprisnil (0.5, 1.5, 5, 10 and 25 mg). All doses showed similar positive effects on pain, whereas the effect on bleeding patterns was dose-dependent.

3.3 Premenstrual syndrome Starting from the observation that premenstrual syndrome occurs mostly during the luteal phase, although no constant or consistent abnormality of basal or stimulated hormones has so far been identified [104,105] , Schmidt et al. [106] hypothesised that ‘an unidentified physiologic abnormality during the late luteal phase’ may cause premenstrual syndrome. To test their hypothesis they administered mifepristone to 14 women with proven syndrome either at a dose of 25 mg daily, starting on day 7 after the LH surge or of 12.5 mg daily in combination with 2000 IU of commercial

human chorionic gonadotrophin (hCG). The two treatments were continued for 3 days: seven women served as controls.

No statistically significant change was found in the pattern of symptom appearance in the three groups and no correlation could be established between their hormonal profiles and symptoms’ scores. For this reason, Schmidt et al. [106] concluded a ‘lack of relevance of late luteal phase biology to the causation of PMS’, underlining once more the lack of scientific rationale for the use of progesterone or progestins in this condition.

This line of research does not seem to have been pursued further.

3.4 Assisted reproduction technology One of the problems encountered in controlled ovarian stimulation, as used in most assisted reproduction technology protocols, is a premature LH surge. Several methods are employed in order to avoid this problem and preliminary data exist on the effect of co-treatment with 40 mg of mifepristone daily on endometrial receptivity. In one study, following administration of human follicle-stimulating hormone alone or together with mifepristone (5 mg/day), the latter caused a temporary delay in the growth of the dominant follicle, with postponement of ovulation [107] .

A second study was conducted on oocyte donors and compared the action of RU 486 to that of a long protocol with GnRH [108] . Women receiving mifepristone were randomly assigned to a final trigger with or without hCG. No LH surge was observed in any subject treated with mifepristone. Their serum progesterone levels on the day of the final stimulation with hCG were below the cut-off level (1.2 ng/ml) in all subjects in the mifepristone group. The mean numbers of cumulus–oocyte complexes retrieved were 11.6 ± 6.6 and 19.6 ± 11.8 in the subgroups treated with RU 486/hCG and RU 486 alone, respectively. The mean percentages of metaPhase II, metaPhase I and germinal vesicle stage oocytes were 86.2, 6.9 and 3.4% in the mifepristone group and 68.4, 6.1 and 11.2% in the control group. In the mifepristone group not triggered by hCG an endogenous LH surge was not observed nor were oocytes obtained. Histological evaluation of endometrial samples in patients treated with mifepristone and hCG showed normal development whereas in patients treated with mifepristone only there was a complete arrest of the endometrial maturation. The results of this preliminary study seem to indicate that mifepristone is effective in preventing a premature LH surge and/or premature luteinisation. At the same time, endometrial receptivity may be a problem and requires further evaluation.

4. Conclusions

Results to date on the development of oral contraceptives based on the administration of an SPRM have been disappointing, whereas, when used as an emergency contraceptive, mifepristone at least shows great potential.

https://www.researchgate.net/publication/13623171_Preliminary_report_on_the_treatment_of_endometriosis_with_low-dose_mifepristone_RU_486?el=1_x_8&enrichId=rgreq-37a7f0b39913324f8d95ba8e043a2f89-XXX&enrichSource=Y292ZXJQYWdlOzIzMjQ0MDM5O0FTOjEyMDIzMDc0MzM4NDA2NUAxNDA1Njc2NjUxNzk2

https://www.researchgate.net/publication/14643676_Treatment_of_endometriosis_with_the_antiprogesterone_mifepristone_RU486?el=1_x_8&enrichId=rgreq-37a7f0b39913324f8d95ba8e043a2f89-XXX&enrichSource=Y292ZXJQYWdlOzIzMjQ0MDM5O0FTOjEyMDIzMDc0MzM4NDA2NUAxNDA1Njc2NjUxNzk2

https://www.researchgate.net/publication/21438379_Endocrine_responses_to_long-term_administration_of_anti-progesteron_RU486_in_patients_with_pelvic_endometriosis?el=1_x_8&enrichId=rgreq-37a7f0b39913324f8d95ba8e043a2f89-XXX&enrichSource=Y292ZXJQYWdlOzIzMjQ0MDM5O0FTOjEyMDIzMDc0MzM4NDA2NUAxNDA1Njc2NjUxNzk2

https://www.researchgate.net/publication/11416903_Selective_progesterone_receptor_modulators_SPRMs_A_novel_therapeutic_concept_in_endometriosis?el=1_x_8&enrichId=rgreq-37a7f0b39913324f8d95ba8e043a2f89-XXX&enrichSource=Y292ZXJQYWdlOzIzMjQ0MDM5O0FTOjEyMDIzMDc0MzM4NDA2NUAxNDA1Njc2NjUxNzk2




Several applications of SPRMs in reproductive medicine were initially reported with great optimism, whereas subsequently there has been, almost invariably, a lack of properly constructed follow-up studies. For this reason, large comparative trials are badly needed in order to evaluate the usefulness of SPRMs in the medical treatment of endometriosis and uterine leiomyomata, as well as in assisted reproduction.

5. Expert opinion

For almost two decades several groups, including the WHO and the Population Council, have attempted the development of an oral contraceptive based on the administration of mifepristone. Unfortunately, to date the results have been disappointing: low-dose regimens either cause bleeding irregularities, do not block ovulation or alter the amount of menstrual bleeding, whereas higher doses not only cause anovulation but also amenorrhoea. The latter may be a welcome attribute in certain cultural settings, whereas women who consider amenorrhoea as ‘unphysiological’ may find it difficult to accept. Daily administration of RU 486 produces significant changes in endometrial biochemistry: these modifications are not sufficient to prevent pregnancy and mifepristone seems to have agonistic action on the endometrium. This is indicated inter alia by the observation of cystic glandular dilatation of the endometrium. It is true that small studies have shown some potential with 2 and 5 mg daily, but the high incidence of amenorrhoea may limit the acceptability of this approach. Indeed, when daily RU 486 was compared to the so-called ‘mini-pill’ (low-dose progestin given alone in a continuous fashion) significant differences in bleeding patterns between the two regimens were observed. It seems therefore that the data gathered so far do not lend themselves to great optimism for this application of mifepristone and, given its association with medical interruption of pregnancy, the pharmaceutical industry has been reluctant to engage in any major research and development effort. Even when given in a sequential regimen with a progestin, in spite of great initial expectations, it is doubtful that, mifepristone at least, will ever become an effective and acceptable oral contraceptive.

Finally, the proposal to administer RU 486 on a weekly basis appears extremely problematic and, correctly, this approach has been all but abandoned.

Certainly not everyone is pessimistic about the possibility of using RU 486 for contraception and efforts in this direction continue.

In this context, studies in non-human primates raised great hope that daily administration of onapristone (considered a pure antiprogestin) might lend itself to being a satisfactory contraceptive. Indeed, modulation of endometrial receptivity might be a promising approach in developing new fertility-regulating agents, since it allows a contraceptive effect specifically targeted at the endometrium. Unfortunately,

the manufacturer, worried about liver toxicity, discontinued the development of the compound.

An entirely different picture is that provided by efforts aimed at developing SPRMs (and mifepristone in particular) as a ‘postcoital’ or ‘day-after’ pill, more correctly named today as ‘emergency contraception’. The data gathered by the WHO have proven that RU 486 at a dose as low as 10 mg, when given up to 5 days after unprotected intercourse, can prevent the establishment of pregnancy more constantly than either oestrogen–progestin (now abandoned) or progestin-only methods. Here again we are dealing with a highly controversial issue: those who believe that pregnancy begins at syngamy are not willing to accept a modality that may act after fertilisation by preventing implantation. The problem is further complicated by recent experimental data showing that, whereas progestin-only emergency contraception methods act mostly if not exclusively before fertilisation, antiprogestins clearly have the ability to prevent the implantation of a fertilised ovum.

The application of SPRMs to gynaecological conditions is an area that raised great expectation because, in theory at least, these compounds lend themselves to long-term use, since they do not cause severe hypo-oestrogenism, a condition unacceptable for young women if prolonged for more than 6 months. Yet, the early small studies on the effects on fibroids by the group of Sam Yen in La Jolla have not been followed by systematic placebo-controlled studies for more than a decade. This situation has been created, among other reasons, by controversy over owner ship and production. Even now that work has resumed the field does not seem very active: a search of the US Government clinical trials site [109] indicated that, out of 42 clinical studies being conducted in the US with mifepristone, only three were for the indication ‘fibroids’ (one completed, one inactive and one actively recruiting). Published information is very promising but is limited to just over 200 patients distributed over seven studies. A negative feature of long-term treatment is the possible occurrence of endometrial hyperplasia, although it is not known whether this can be prevented with low dosages. Interesting results have been obtained using asoprisnil, which is capable of inducing amenorrhoea and a reduction in fibroid volume in a dose-dependent manner.

In addition, in the case of long-term management of pain caused by endometriosis, the selective inhibition of endometrial proliferation without the damaging effects of oestrogen deprivation makes SPRMs particularly interesting. Both mifepristone and asoprisnil have been used with positive results: here again, large, comparative or placebo-controlled studies are badly needed.

Declaration of interest

The authors state no conflict of interest and have received no payment in the preparation of this manuscript.



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Affi liation Giuseppe Benagiano 1 MD PhD FACOG(hon) FRCOG(ad eundem) Hon Sen(Szeged) , Carlo Bastianelli 2 MD PhD & Manuela Farris † 3 MD PhD † Author for correspondence 1 Professor and Dean University ‘la Sapienza’, Postgraduate School of Gynaecology and Obstetrics, Policlinico Umberto I ° , Viale Regina Margherita 245, 00161 Roma, Italy 2 Associate Professor University ‘la Sapienza’, Department of Gynaecology and Obstetrics, Policlinico Umberto I ° , Viale Regina Margherita 245, 00161 Roma, Italy 3 Research Associate University ‘la Sapienza’, Department of Gynaecology and Obstetrics, Policlinico Umberto I ° , Viale Regina Margherita 245, 00161 Roma, Italy Tel: +39 06 490 398 ; Fax: +39 06 4997 2455 ; E-mail: [email protected]






































Selective progesterone receptor modulators 2: use in reproductive medicine

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