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Academic research paper on topic "Biodegradability Evaluation of Polymers by ISO 14855-2"

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European Journal of Obstetrics & Gynecology and Reproductive Biology

journal homepage: www.elsevier.com/locate/ejogrb

Review

Progesterone and progesterone receptor modulators in the management of symptomatic uterine fibroids

Vikram Sinai Talaulikar*, Isaac Manyonda

Department of Obstetrics & Gynaecology, St. George's Hospital and University of London, Cranmer Terrace, Tooting, London SW17 0RE, United Kingdom

abstract

The majority of symptomatic uterine fibroids are currently treated by surgical interventions (myomectomy or hysterectomy) or radiological treatments (uterine artery embolisation or focussed ultrasound surgery). None of these treatments is a panacea, and what is conspicuous is the lack of an effective long-term medical therapy for a disorder so common among women of reproductive age. It has been known for some time that progesterone and its receptors enhance proliferative activity in fibroids and this has raised the possibility that anti-progestins and (PRMs) could be useful in the medical management of fibroids. Some of the compounds which have produced promising results in recent clinical trials or research studies include mifepristone, CDB-4124 (telapristone), CP-8947, J-867 (asoprisnil) and CDB-2914 (ulipristal acetate or UA). UA has recently completed Phase III clinical trials with very encouraging results, and has now acquired a licence for clinical use in Europe. While considerable research has yet to be done on the long-term safety and efficacy of UA there is nevertheless good reason for optimism on the emergence of effective medical therapy in the form of UA and possibly other PRMs.

© 2012 Elsevier Ireland Ltd. All rights reserved.

article info

Article history: Received 29 January 2012 Received in revised form 3 June 2012 Accepted 25 July 2012

Keywords:

Progesterone receptor modulators

Fibroids

Contents

1. Introduction..........................................................................................................................................................................................................135

2. Progesterone, the progesterone receptor and receptor antagonists/modulators................................................................................................136

3. The levonorgestrel intrauterine system (LNG-IUS)..............................................................................................................................................136

4. Progesterone receptor modulators (PRMs)..........................................................................................................................................................137

4.1. Mechanisms of action................................................................................................................................................................................137

4.2. Evidence for effectiveness of PRMs in treatment of uterine fibroids......................................................................................................137

4.3. Mifepristone (RU-486)..............................................................................................................................................................................137

4.4. CDB-4124 (telapristone)............................................................................................................................................................................138

4.5. J-867 (asoprisnil)......................................................................................................................................................................................138

4.6. CDB-2914 (ulipristal acetate or UA)..........................................................................................................................................................138

5. Adverse effects and limitations associated with long-term use of PRMs..........................................................................................................138

5.1. Endometrial hyperplasia and thickening..................................................................................................................................................138

6. Conclusion............................................................................................................................................................................................................139

References............................................................................................................................................................................................................139

1. Introduction

Fibroids are the most common tumour of women during reproductive life. They are symptomatic in 50% of women who have them, with the peak incidence of symptoms occurring among women in their 30s and 40s [1]. Symptoms include menstrual

* Corresponding author. Tel.: +44 0208725 3695/2858. E-mail address: vtalauli@sgul.ac.uk (V.S. Talaulikar).

0301-2115/$ - see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2012.07.023

disturbance (commonly menorrhagia and dysmenorrhoea), pressure symptoms such as increased urinary frequency, pelvic pain, constipation and potential interference with reproduction. Fibroids can also cause symptoms (including abnormal bleeding) in the menopause [2]. Thus although benign, fibroids have a major impact on women's health and their quality of life.

Current treatment options for the woman with symptomatic fibroids include abdominal hysterectomy, conventional abdominal myomectomy, laparoscopic and vaginal myomectomy [3,4] and the radiological interventions uterine artery embolisation (UAE)

[5] and magnetic resonance-guided focused ultrasound surgery (MRgFUS) [6]. Hysterectomy is unacceptable to the woman wishing to retain fertility potential, while conventional myomectomy is associated with risks of adhesions, morbidity and indeed mortality. Both laparoscopic and vaginal myomectomy require skills that are not commonplace and there are limitations on the size and number of fibroids that can be treated by these modalities. UAE is now widely used in the United States (US) and Western Europe but is still under evaluation, has a range of complications including premature ovarian failure, chronic vaginal discharge and in rare cases pelvic sepsis, and may have limited efficacy where the fibroids are large [7]. MRgFUS, which has major cost implications by its requirement for MRI, was approved by the US Food and Drug Agency (FDA) in 2004, while the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom has recommended that the procedure be used in an audit and research setting [8]. Thus none of the available treatments is a panacea. Given the choice, many women would opt to avoid major surgery or indeed even the less invasive radiological procedures. There is therefore a need for medical therapy that has efficacy equivalent or superior to surgery, does not interfere with reproduction, has minimal side effects and is relatively cheap.

Current medical therapeutic approaches exploit the observations that uterine fibroids have significantly increased concentrations of both estrogen and progesterone receptors compared with normal myometrium [9,10], and that ovarian steroids influence fibroid growth. Most available therapies are therefore hormonal or act on the relevant hormones or their receptors to interfere with fibroid growth. Gonadotrophin-releasing hormone (GnRH) analogues have been the most widely used, and while they do cause fibroid regression, they can only be used in the short term, as temporising measures in the perimenopausal woman, or pre-operatively to reduce fibroid size and influence the type of surgery, restore haemoglobin levels and apparently reduce blood loss at operation. They are notorious for rebound growth of the fibroids upon cessation of therapy and have major side-effects. Selective estrogen receptor modulators (SERMs) such as raloxifene have been shown to induce fibroid regression in post- but not pre-menopausal women. Experience with these drugs is limited, however, and they are associated with significant side effects. There are also suggestions that the levonorgestrel intrauterine system (LNG-IUS) can cause dramatic reduction in menstrual flow in women with fibroids, but as yet there are no randomised trials of its use in these women, where rates of expulsion of the device appear to be high. This review discusses the role of progesterone and progesterone receptor modulators (PRMs) in the treatment of symptomatic uterine fibroids.

2. Progesterone, the progesterone receptor and receptor antagonists/modulators

Progesterone plays a crucial part in human reproductive physiology. Its physiological effects impact the processes of endometrial differentiation, ovulation, implantation, successful development of the embryo, development of the mammary gland and regulation of central signals from the hypothalamic-pituitary (HP) axis. The effects of progesterone on target tissues are mediated via the progesterone receptor (PR), which belongs to the nuclear receptor family [11]. The PR exists as three separate isoforms (A, B and C) expressed from a single gene [11]. The PR functions as a ligand-activated transcription factor to regulate the expression of specific sets of target genes. PR antagonists oppose the biological actions of progesterone by inhibiting PR activation. Progesterone has dual actions on fibroid growth. It stimulates growth by up-regulating EGF and Bcl-2 and down-regulating tumor necrosis factor-alpha expression while

it inhibits growth by down-regulating IGF-I expression [12,13]. While it has long been established that estrogen promotes fibroid growth, recent biochemical and clinical studies have suggested that progesterone and the PR may also enhance proliferative activity in fibroids [12,13]. These observations have therefore raised the possibility that anti-progestins and agents or molecules that modulate the activity of the PR could be useful in the medical management of uterine fibroids.

Since the emergence of mifepristone (RU-486), the first PR antagonist, more than 25 years ago, hundreds of steroidal as well as non-steroidal compounds displaying progesterone antagonist (PA) or mixed agonist/antagonist activity have been synthesised. Collectively, they are known as progesterone receptor modulators (PRMs). These compounds have a huge potential for use in the treatment of a number of pathological conditions of the female reproductive system including uterine fibroids, endometriosis and dysfunctional uterine bleeding, and as potential contraceptives. Some of the PRMs which have been the subject of recent clinical trials or research studies in relation to fibroid treatment include mifepristone, CDB-4124 (telapris-tone), CP-8947 and J867 (asoprisnil) and CDB-2914 (ulipristal acetate).

3. The levonorgestrel intrauterine system (LNG-IUS)

The LNG-IUS, which first appeared on the market in 1990s, has transformed the management of menorrhagia over the last two decades. It proved highly effective in reducing menstrual blood loss and is now considered an alternative to the surgical treatment of menorrhagia [14]. The system consists of a T-shaped intrauterine device sheathed with a reservoir of levonorgestrel that is released at the rate of 20 mcg/day. Hormone release at the target organ minimises systemic side effects. It exerts its clinical effect by preventing endometrial proliferation and consequently reduces both the duration of bleeding and the amount of menstrual loss [15]. The LNG-IUS has been shown to reduce menstrual blood loss by 94% by three months and to be well accepted by most women when used for menorrhagia [16]. In a landmark study, Lahteenmaki et al. [17] randomised women on surgical waiting lists to continue with their current medical regimen or to use an LNG-IUS: 64% women using the LNG-IUS cancelled their surgery to continue using the LNG-IUS, compared to only 14% of women not using the system. Other studies followed which showed that the LNG-IUS was a cost effective alternative to hysterectomy during the first year [18,19]. At present there are no randomised trials of the use of LNG-IUS in menorrhagic women with uterine myomas. There are of course reports of its use in these women, with striking reductions in menorrhagia being reported [20]. Although some women with large intramural myomas had spontaneous expulsion of LNG-IUS at various intervals, they wanted re-insertion of the device because of remarkable reduction in menorrhagia [21]. Significant increases in haemoglobin levels were observed after insertion of the devices, but no significant differences were noted in myoma volume and uterine volume, as assessed by MRI examination pre-treatment and at 12 months of use [20,21]. The absence of any change in myoma volume is intriguing, since theoretically it might be expected that the progesterone released from the device could stimulate fibroid growth. There is therefore an obvious need for further research in this area [22]. It would be interesting to establish whether expulsion of the device is dependent upon the size or number or location of the fibroids: it is reasonable to assume that submucous fibroids, or large intramural fibroids distorting the cavity, would be associated with an increased risk, but at present there are no data to provide the evidence base to better advise patients.

4. Progesterone receptor modulators (PRMs)

4.1. Mechanisms of action

The following mechanisms of action have been proposed for the

effect of PRMs on fibroids (Fig. 1):

(a) Ulipristal down-regulates the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF) and their receptors in cultured fibroid cells [23] resulting in suppression of neovascularisation, cell proliferation and survival [12].

(b) Ulipristal and asoprisnil inhibit proliferation of cultured fibroid cells and induce apoptosis by up-regulating cleaved caspase 3 and down regulating Bcl-2 [12,23,24].

(c) Ulipristal also increases the expression of matrix metallopro-teinases (MMPs) and decreases the expression of tissue inhibitor of metalloproteinases (TIMPs) and collagens in cultured fibroid cells. This may reduce collagen deposition in the extracellular spaces of fibroids, impairing tissue integrity [12,23,25].

(d) CP-8947 inhibits leiomyoma cell proliferation and decreases extracellular matrix (ECM) component production, without disrupting myometrial cell proliferation [26].

(e) Asoprisnil and ulipristal have been shown to modulate the ratio of progesterone receptor isoforms (PR-A and PR-B) in cultured leiomyoma cells [27]. They decreased the cell viability; suppressed the expression of growth factors, angiogenic factors and their receptors in those cells; and induced apoptosis by activating the mitochondrial and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways and eliciting endoplasmic reticulum stress. Furthermore, these compounds suppressed types I and III collagen synthesis in cultured leiomyoma cells without affecting such synthesis in cultured normal myometrial cells [27].

(f) Mifepristone and asoprisnil have also been associated with a

decrease in uterine artery blood flow. Daily doses of mifepristone (2-5 mg), telapristone (12.5-50 mg) and ulipristal (5-10 mg) inhibit ovulation in normal women [12,28-31] but asoprisnil, in contrast, is not so effective in inhibiting ovulation [32]. The amenorrhea occurring with PRMs is associated with levels of estradiol in the early follicular phase range of the normal menstrual cycle [12,28-33].

4.2. Evidence for effectiveness of PRMs in treatment of uterine fibroids

A number of clinical trials have established the potential of PRMs in the treatment of uterine fibroids. They are associated with a reduction in pain, bleeding, size of fibroids and overall improvement in quality of life. Unlike long-acting GnRH analogues, they do not have the drawbacks of the profound estrogen deficiency and decrease in bone mineral density.

4.3. Mifepristone (RU-486)

Most readers will be familiar with mifepristone as the drug used for medical termination of pregnancy, with or without misopros-tol. Mifepristone is a high progesterone receptor affinity anti-progestin. For purposes of pregnancy termination, it is used in doses of 200-800 mg, and its efficacy is well proven. Early reports of the use of mifepristone for the treatment of fibroids date back to 2002, when De Leo et al. used doses ranging from 12.5 to 50 mg daily and reported a reduction in uterine/fibroid volume of 4050%, with amenorrhea in most subjects [34]. This report was corroborated by a paper a year later from a group who used mifepristone at a dose of 5 or 10 mg per day for one year, and found that it was effective in decreasing mean uterine volume by 50%, while amenorrhea occurred in 40-70% of the subjects [35]. Adverse effects included vasomotor symptoms, but no change in bone mineral density was noted. Hot flashes were increased over

Fig. 1. Mechanisms of action of progesterone receptor modulators on uterine fibroids (ER - estrogen receptors, PR - progesterone receptors and AR - androgen receptors).

baseline in the 10 mg group, but 5 mg per day did not increase the incidence of vasomotor symptoms. Simple hyperplasia was noted in 28% of the women. This study therefore suggested that a dose as low as 5 mg per day of mifepristone may be efficacious for the treatment of uterine fibroids, with few side effects [35]. Antiglucocorticoid effects of long term use of mifepristone are usually only seen with doses exceeding 200 mg daily [36]. The same group of researchers then followed up their preliminary findings with a randomised controlled trial (RCT) on the use of mifepristone for the treatment of uterine fibroids. This was a small study which included 42 women in a double-blind placebo-controlled study design over a period of 6 months [37]. They reported that overall quality of life was improved significantly, and anaemia rates and uterine volume were reduced significantly. The hyperplasia seen in some women may limit the use of this drug among those desiring a long-term medical therapeutic alternative. The apparent effectiveness of mifepristone, however, in reducing myoma volume and improving fibroid-related symptoms and quality of life, and the minimal side-effects, all point to a need for a large RCT with sufficient power to define its true place in the medical management of uterine fibroids. A combination of mifepristone and the LNG-IUS could prove especially useful as the IUS would obviate the development of endometrial hyperplasia while also promoting a reduction in menstrual flow. In another RCT, 100 women were assigned to mifepristone 5 or 10 mg daily for 3 months without a placebo group: with both doses, there were equivalent reductions in fibroid and uterine volumes and symptomatic improvements [38].

4.4. CDB-4124 (telapristone)

A clinical trial (phase I/II) evaluated the efficacy of telapristone in symptomatic fibroids. This small 3-month study comprising 30 women, compared oral doses of 12.5, 25 and 50 mg telapristone with the GnRH analogue leuprolide and a placebo [39]. There was a significant reduction in tumor size and reduced bleeding with telapristone treatment.

4.5. J-867 (asoprisnil)

Asoprisnil has high tissue selectivity and binds to progesterone receptors with a 3-fold greater binding affinity than progesterone [40]. The initial phase I studies established that asoprisnil induced a reversible suppression of menstruation, while having variable effects on ovulation [32]. The phase II multi-centre double-blind placebo-controlled studies by the same group of researchers compared the efficacy and safety of three doses (5, 10 and 25 mg and placebo) in 129 women over 12 weeks [41,42]. Asoprisnil reduced the uterine and fibroid volumes in a dose dependent manner. There was a dose dependent decrease in menorrhagia scores in women with menorrhagia at baseline, while amenorrhea rates increased as the dose increased (28.1% with 5 mg, 64.3% with 10 mg and 83.3% with 25 mg), but with no increase in the rates of unscheduled bleeding in all three asoprisnil groups. Compared to placebo, haemoglobin levels were improved in all three treatment groups, while adverse effects were evenly distributed. The initial clinical trials of asoprisnil suggested endometrial thickening to be one of the important side effects of the drug. Overall safety data available so far, however, have been reassuring and its impact on bone mineral density, fertility, recurrence rates of fibroids and endometrial hyperplasia are still under evaluation.

4.6. CDB-2914 (ulipristal acetate or UA)

In Phase II and III clinical trials, a number of issues have been addressed using UA. In the first trial [43] in which UA was given at

10 mg or 20 mg in comparison against placebo for three cycles, UA showed a 92% reduction in bleeding versus 19% with placebo. Leiomyoma volume was significantly reduced with UA (29% versus 6%; p = 0.01). UA eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles 20% on UA versus 83% with placebo; p = 0.001). UA also improved the concern scores of the uterine leiomyoma symptom quality of life subscale (p = 0.04). One woman on UA developed endometrial cystic hyperplasia without evidence of atypia. No serious adverse events were reported. UA did not suppress estradiol and there were no differences in serum estradiol levels between the treatment and placebo groups (median estradiol was greater than 50 pg/ml in all groups). The numbers studied were small, however, with 22 patients being allocated and 18 completing the three cycles or 90-120 day trial [43]. A more recent randomised, double blind, placebo controlled trial of efficacy and tolerability has also demonstrated positive results when UA was administered for 3-6 months, showing good control of bleeding, reduction in fibroid size, and improvement in quality of life in the treatment group [44].

UA has recently successfully completed two Phase III clinical trials (PEARL I and II) in Europe, demonstrating its efficacy and safety for the treatment of symptomatic uterine fibroids in patients eligible for surgery [45,46]. PEARL I compared treatment with oral UA for up to 13 weeks at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) with placebo (48 women) in patients with fibroids, menorrhagia and anaemia. All patients received iron supplementation. The co-primary efficacy end points were control of uterine bleeding 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 UA, 92% of those receiving 10 mg of UA, and 19% of those receiving placebo (p < 0.001 for the comparison of each dose of UA with placebo). Treatment with UA for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids. PEARL II was a double-blind non-inferiority trial, which randomly assigned 307 patients with symptomatic fibroids and excessive uterine bleeding to receive three months of daily therapy with oral UA (at a dose of either 5 mg or 10 mg) or once-monthly intramuscular injections of the GnRH analogue 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 pre-specified non-inferiority margin of -20%. Uterine bleeding was controlled in 90% of patients receiving 5 mg of UA, in 98% of those receiving 10 mg, while the figure for leuprolide acetate was 89%. Both UA doses were non-inferior to once monthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes [46].

5. Adverse effects and limitations associated with long-term use of PRMs

5.1. Endometrial hyperplasia and thickening

A National Institute of Health (NIH) sponsored workshop evaluated endometrial specimens from women receiving mifepristone, asoprisnil and UA [12,47,48]. Pathologists were blinded to agent, dose and exposure interval. It was concluded that there was little evidence of mitosis, consistent with the anti-proliferative effect of PRMs. No biopsy demonstrated atypical hyperplasia. There was asymmetry of stromal and epithelial growth and prominent cystically dilated glands with both admixed estrogen (mitotic) and progestin (secretory) epithelial effects. This histology has not previously been encountered in clinical practice. The panel designated these changes as PRM associated endometrial changes (PAECs) [12,47,48]. Despite the paucity of mitoses, pathologists may associate the cystic glandular dilatation observed with PRMs

with simple hyperplasia and should be aware of the potential diagnostic pitfalls of misdiagnosing hyperplasia in women receiving PRMs [12,49]. In another study, biopsies were obtained from 58 premenopausal women participating in clinical trials of the telapristone. Biopsies were obtained at 3 and 6 months, and women were receiving daily doses of oral therapy that ranged from 12.5 to 50 mg. Of the 174 samples, 103 contained histologic changes not seen in the normal menstrual cycle [50]. Whereas the majority of the histology was atrophic, novel cystic changes were seen with increasing doses. Cystically dilated glands with mixed secretory and mitotic features were noted [50]. These lesions are not considered to be premalignant and no malignancies were found.

A few studies have reported endometrial thickening detected on ultrasound after use of high or low dose mifepristone [51,52]. During three months' treatment with ulipristal in normal women, no thickening was observed and examination of hysterectomy specimens after three months of asoprisnil (10 or 25 mg) showed that when compared with placebo, there was a trend for decreased endometrial thickness [12,31]. With use of telapristone in the treatment of fibroids, there was a minimum increase in endometrial thickness of 3.3 and 4.2 mm with the 12.5 and 25 mg doses, respectively, after three months of treatment [12]. It has been suggested that, unlike in the situation where there is unopposed estrogen effect, the endometrial thickening in women on PRMs is related to cystic glandular dilation and not endometrial hyperplasia. The overall evidence emerging from the recent clinical trials regarding the safety of PRMs appears to be reassuring. Clinicians detecting endometrial thickening in women treated with PRMs need to be aware that administration of PRMs for longer than 3 months may lead to endometrial thickening. This is related to cystic glandular dilation, not endometrial hyperplasia and pathologists need to be aware of PAEC and avoid misclassifying the appearance as hyperplasia. It is also important to consider the limitations of the current data while describing the effects of PRMs on the endometrium. Most existing studies have described the endometrial changes over short periods (months) of follow-up, but atypical hyperplasia and possibly malignant change take years to develop. Long term studies are therefore necessary to evaluate such outcomes.

Although breakthrough bleeding has been reported as one of the side effects of PRMs, sufficient data assessing their long term use are not available. It is also argued that PRMs are not useful for the treatment of large fibroids as they cause only a modest decrease in their size. Larger clinical trials, however, with varying doses and duration of therapy of PRMs in future will be able to provide a definite answer to this question.

6. Conclusion

The ideal medical therapy for the treatment of symptomatic fibroids is arguably a tablet that is taken by mouth, once a day or even better still, once a week, with minimal if any side effects, which rapidly induces fibroid regression and thus a resolution of symptoms but without affecting fertility. While such a magic bullet does not yet exist, PRMs have for years tantalized the clinician with their simplicity of administration, potentially minimal side effects profile and likely low costs. Among the PRMs, ulipristal acetate has undoubtedly stolen the march on its competitors. The manufacturer-sponsored Pearl I and II trials reported that whether given at a 5 mg or 10 mg dose, ulipristal is highly effective at reducing menstrual blood loss, effecting amenorrhoea in 75% of recipients within 10 days, and has many attributes that arguably render it not only non-inferior but potentially superior to GnRH analogues, not least the absence of estrogen suppression and its consequences, with a more rapid return of menstruation upon cessation of

therapy, and a more persistent shrinkage of fibroids at six months post-treatment. Researcher-led studies are now required to reproduce these data, and to evaluate the long-term efficacy and safety, especially with regard to the endometrium, metabolism and of course reproductive function. The manufacturers have secured a licence for the use of ulipristal acetate in most of Western Europe including the UK, and thus a variety of trials can now be undertaken that should help establish the true role of UA. It would be most unfortunate, however, if research on other PRMs were to cease, since the quest for the magic bullet must be sustained to definitively treat the commonest tumour of women of reproductive age.

Conflicts of interest

Neither of the authors has any conflicts of interest to declare. No funding was received for preparation of this manuscript.

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