Progesterone Receptor Modulator-associated Endometrial Changes Research Articles

Pharmacodynamics and pharmacokinetics of a copper intrauterine contraceptive system releasing ulipristal acetate: A randomized proof-of-concept study

ObjectivesTo assess pharmacodynamic and pharmacokinetic outcomes of a novel copper (Cu) intrauterine system (IUS) releasing ulipristal acetate (UPA) in healthy women. Study DesignIn this single-blinded, randomized proof-of-concept study, ovulatory women received one of three Cu-IUSs releasing low-dose UPA (5, 20 or 40 µg/d) for 12 weeks. The study included a baseline cycle, three 4-week treatment-cycles and 2 recovery cycles. Primary outcomes included effects of the IUS on bleeding profile, ovarian function, and the occurrence of progesterone receptor modulator associated endometrial changes (PAEC). Pharmacokinetics and safety profile were secondary outcomes. We compared outcomes in treatment-cycle 3 with baseline, using generalized linear mixed models with orthogonal contrasts. ResultsWe randomized 29 women (5 µg/d = 10, 20 µg/d = 10, 40 µg/d = 9). All had a successful IUS insertion; 27 completed the 12-week treatment period. Compared to baseline, the mean number of bleeding-only days at treatment-cycle 3 declined by 16.7% in the 5 µg/d group (3.6 vs 3.0, p = 0.66), 40.5% in the 20 µg/d group (4.2 vs 2.5, p = 0.14), and 77% in the 40 µg/d group (3.9 vs 0.9, p = 0.002). Most women reported reduction in the amount of bleeding: 4/8, 8/10, and 7/9 for the 5 µg/d, 20 µg/d, and 40 µg/d groups, respectively. During IUS use, ovulation occurred in most cycles [5 µg/d: 23/24 (96%), 20 µg/d: 26/30 (87%), 40 µg/d: 22/27 (81%)]. The frequency of PAEC at IUS removal was 1/10 (10%), 1/10 (10%) and 4/9 (44%) in the 5 µg/d, 20 µg/d, and 4 0 µg/d groups, respectively. No serious adverse events occurred. ConclusionsReduction in bleeding, low incidence of PAEC, and no serious adverse events are reassuring findings of the novel Cu-UPA-IUS. The 20 µg/d seems the lowest dose promoting a favorable bleeding profile and limiting PAEC. ImplicationsThe preliminary results of this short-term study of a novel copper intrauterine system (IUS) delivering ulipristal acetate showed reduction of bleeding, low incidence of progesterone receptor modulator associated endometrial changes, and absence of serious adverse events. By preventing copper-induced increase in bleeding, this IUS could provide a noncontraceptive benefit, especially for women with low hemoglobin.

Glucose and fatty acid metabolism involved in the protective effect of metformin against ulipristal-induced endometrial changes in rats

Ulipristal acetate (UPA) is effective in the treatment of uterine fibroids. However, its clinical use is hampered by the development of pathologic progesterone receptor modulator-associated endometrial changes (PAECs). The current study was designed to test the hypothesis that UPA-induced PAECs are associated with deranged expression of some metabolic genes. In addition, metformin can mitigate UPA-induced PAECs through modulating the expression of these genes. In the present study, twenty-eight female non-pregnant, nulligravid Wistar rats were treated with UPA (0.1 mg/kg/day, intragastric) and/or metformin (50 mg/kg/day, intragastric) for 8 weeks. Our results demonstrated that co-treatment with metformin significantly reduced UPA-induced PAECs. In addition, co-treatment with metformin and UPA was associated with significant increase in the Bax and significant reduction in Bcl-2, PCNA, Cyclin-D1and ER-α as compared to treatment with UPA alone. Furthermore, treatment with UPA alone was associated with deranged expression of 3-phosphoglycerate dehydrogenase (3-PHGDH), glucose-6-phosphate dehydrogenase (G6PD), transketolase (TKT), fatty acid synthase (FAS) and CD36. Most importantly, co-treatment with metformin markedly reduced UPA-induced altered expression of these metabolic genes in endometrial tissues. In conclusion, UPA-induced PAECs are associated with altered expression of genes involved in cell proliferation, apoptosis, estrogen receptor, glucose metabolism and lipid metabolism. Co-treatment with metformin abrogated UPA-induced PAECs most likely through the modulation of the expression of these genes.

Effects of the levonorgestrel intrauterine system on the endometrium after long-term exposure to mifepristone: Secondary outcomes of a randomized controlled trial

ObjectiveLong-term treatment with progesterone receptor modulators (PRM) is associated with a distinct histological entity termed progesterone receptor modulator associated endometrial changes (PAEC). While accumulating evidence implies that these changes are benign and reversible after cessation of treatment, there are currently no data underpinning their development. Consequently, as a precaution, endometrial shedding is recommended after long-term PRM intake. Avoiding endometrial shedding after treatment with a PRM and prior to the start of a progestin treatment would be beneficial for women in reproductive age to avoid pregnancy and bleeding. However, the endometrial morphology with such a treatment regimen is unknown. The aim of this study was to delineate the endometrial morphology following continuous long-term treatment with the PRM mifepristone and subsequent placement of a levonorgestrel intrauterine system (LNG-IUS) without prior shedding of the endometrium. Study designThis study reports the secondary outcome from a double-blinded randomized controlled trial conducted at Karolinska University Hospital, Sweden, November 2009 to January 2015. Healthy women aged 18–43 years with regular menstrual cycles were included. Eligible women were randomized to receive either 50 mg of mifepristone (n = 29) or a comparator (n = 29), every other day for two months followed by insertion of an LNG-IUS 52 mg. Endometrial biopsies were obtained at baseline and three months after placement of the device. The samples were histologically assessed. The main outcome measure of this sub-study was the endometrial morphology including presence of PAEC three months after LNG-IUS insertion. ResultsNine and eight paired biopsies from the mifepristone and comparator group, respectively, were included in the histological analysis. There were no differences in baseline characteristics between the groups and all baseline endometrial biopsies were physiological. Three months after LNG-IUS placement the endometrial morphology was still benign without PAEC in all samples treated with either mifepristone or comparator. A progestin effect on the endometrium was seen in all samples. ConclusionsPlacement of an LNG-IUS immediately following two months’ treatment with the PRM mifepristone, without any prior shedding of the endometrium, may represent a feasible approach in terms of endometrial safety. However, larger studies are needed to confirm our results.

Selective Progesterone Receptor Modulators-Mechanisms and Therapeutic Utility.

Selective progesterone receptor modulators (SPRMs) are a new class of compounds developed to target the progesterone receptor (PR) with a mix of agonist and antagonist properties. These compounds have been introduced for the treatment of several gynecological conditions based on the critical role of progesterone in reproduction and reproductive tissues. In patients with uterine fibroids, mifepristone and ulipristal acetate have consistently demonstrated efficacy, and vilaprisan is currently under investigation, while studies of asoprisnil and telapristone were halted for safety concerns. Mifepristone demonstrated utility for the management of endometriosis, while data are limited regarding the efficacy of asoprisnil, ulipristal acetate, telapristone, and vilaprisan for this condition. Currently, none of the SPRMs have shown therapeutic success in treating endometrial cancer. Multiple SPRMs have been assessed for efficacy in treating PR-positive recurrent breast cancer, with in vivo studies suggesting a benefit of mifepristone, and multiple in vitro models suggesting the efficacy of ulipristal acetate and telapristone. Mifepristone, ulipristal acetate, vilaprisan, and asoprisnil effectively treated heavy menstrual bleeding (HBM) in patients with uterine fibroids, but limited data exist regarding the efficacy of SPRMs for HMB outside this context. A notable class effect of SPRMs are benign, PR modulator-associated endometrial changes (PAECs) due to the actions of the compounds on the endometrium. Both mifepristone and ulipristal acetate are effective for emergency contraception, and mifepristone was approved by the US Food and Drug Administration (FDA) in 2012 for the treatment of Cushing’s syndrome due to its additional antiglucocorticoid effect. Based on current evidence, SPRMs show considerable promise for treatment of several gynecologic conditions.

Ulipristal Acetate Prior to Surgery for Endometriosis.

Selective progesterone receptor modulators may have a role in the treatment of endometriosis. The aim of this report is to review the effect of ulipristal acetate (UPA) on endometriosis lesions and symptoms in women treated prior to surgery. A pathology review of eutopic endometrium and endometriotic lesions was conducted by two gynecologic pathologists. The main outcome measures reported are pain reduction, amenorrhea, and pathologic progesterone receptor modulator-associated endometrial changes (PAECs). Overall, fifteen women with endometriosis received UPA over a 27-month study period. UPA was administered in an intermittent fashion in the majority of patients while 27% of patients had continuous treatment, between 6 and 24months. Eleven (73%) patients reported amenorrhea on UPA and 11 (92%) of 12 patients with pain reported pain reduction or resolution. Fourteen patients (93%) proceeded with surgical management. Thirteen (93%) patients underwent excision of suspected endometriosis at surgery. Twelve cases (86%) had concurrent eutopic endometrium specimens and PAEC was identified in 58% (n = 7). Among the 14 cases that underwent surgery, a total of 49 extraovarian sites were sampled. Endometriosis was definitively identified in 31 (63%) of these sites. Three cases (21%) showed morphologic features similar to PAEC within foci of endometriosis. All cases of PAEC-like features in endometriosis also had PAEC in the endometrium. These patients had all noted pain reduction and amenorrhea preoperatively. In conclusion, PAECs may be found in endometriosis lesions in patients treated with UPA. Further prospective investigation is required to evaluate the efficacy and safety of SPRMs in women with endometriosis.

Vilaprisan for treating uterine fibroids

ABSTRACTIntroduction: The medical strategy to antagonize myoma size and related-symptoms is to reduce estrogen and progesterone activity on myomas. This can be obtained with the GnRH agonist (GnRHa) or with compounds that antagonize progesterone stimulatory activity on myomas. Selective progesterone receptor modulators (SPRMs) bind progesterone receptor (PR), leading to both agonist and antagonist effects. The result of SPRMs’s action is tissue-specific and it depends on the particular affinity and strength of each SPRM.Area covered: Ulipristal acetate (UPA) is the first SPRM registered for myoma treatment. UPA reduces heavy uterine bleeding within 7 days from the onset of treatment, whereas a longer time is required with GnRHa treatment. Vilaprisan is a novel powerful SPRM. Phase I and II studies give encouraging results on the efficacy of vilaprisan at different doses. Like other SPRMs, vilaprisan induces benign changes of endometrium (PR modulator-associated endometrial changes, PAECs). These disappear as treatment is discontinued. Unlike GnRHa treatment, neither UPA nor vilaprisan induce hypoestrogenism and associated symptoms. Phase III studies are ongoing to confirm efficacy and safety of vilaprisan in long-term treatment of symptomatic fibroids.Expert opinion: It is fundamental to underline the rapidity of action (only 3 days) in the control of myoma-related bleeding.

Safety of treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate

Introduction: During the last decade, there has been increased emphasis on the role of progesterone in the promotion of fibroid growth, as well as heightened interest in modulating progesterone pathways by use of selective progesterone receptor modulators. Among them, ulipristal acetate (UPA) has proved its efficacy in the management of symptomatic myomas by controlling bleeding and inducing amenorrhea, and reducing the size of myomas in the majority of cases.Areas covered: In this review, we summarize published scientific studies exploring evidence of the safety of selective progesterone receptor modulators and particularly UPA, a drug approved for the management of symptomatic uterine fibroids. We focus essentially on endometrial changes induced by UPA, and also evaluate other safety outcomes.Expert opinion: Data from published reports of randomized controlled trials over 5 years have demonstrated that UPA does indeed induce endometrial changes (known as progesterone receptor modulator-associated endometrial changes), but they have been shown to be both benign and reversible.Novel algorithms published very recently provide an extensive overview that may be considered as the latest expert opinion. Thus, in infertile women of reproductive age, two courses of 3 months of UPA are recommended in case of type 2 myomas or multiple myomas distorting the uterine cavity. Subsequent therapy is determined depending on the response and restoration of the uterine cavity. If there is no desire for pregnancy, long-term (four courses) intermittent therapy may be initiated. In case of a good response, treatment is stopped and restarted only if symptoms recur. In premenopausal women wishing to preserve their uterus, four courses of 3 months is the proposed strategy.Contraindications to prescribing UPA include pregnancy, breastfeeding, genital bleeding of unknown etiology of origin other than uterine fibroids, and presence of uterine, cervical, ovarian, or breast cancer.

Place of ulipristal acetate in the management of uterine fibroids: Preoperative treatment or sequential treatment?

Symptomatic uterine fibroids affect 25% of women of childbearing potential and are responsible for various symptoms, mainly menometrorrhagia, pelvic pain and infertility. No currently available medical treatment is able to eradicate fibroids. Two treatments are indicated preoperatively to reduce bleeding and decrease the size of fibroids: GnRH agonists and ulipristal acetate. Ulipristal acetate, a selective progesterone receptor modulator, exerts an antagonist effect on fibroid tissue, inducing apoptosis. It rapidly induces amenorrhoea (after an average of seven days of treatment) and reduces fibroid volume. It causes few adverse effects and, in particular, is associated with a low rate of hot flashes compared to GnRH agonists. Due to its partial antagonist effect on endometrial tissue, endometrial thickening with no glandulocystic atypia is commonly observed during treatment and is reversible after stopping treatment. These specific histological changes are called Progesterone receptor modulator-Associated Endometrial Changes (PAEC). Since February 2012, ulipristal acetate has been approved in Europe for preoperative treatment of symptomatic fibroids for two three-month cycles. The use of ulipristal acetate facilitates surgery or allows modification of the surgical approach (due to a reduction of fibroid volume) and restores normal preoperative hemoglobin. In some cases, the reduction of menometrorrhagia induced by treatment can allow surgery to be postponed. Since May 2015, ulipristal acetate is also indicated as repeated sequential treatment for moderate-to-severe symptoms due to uterine fibroids.

Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium.

STUDY QUESTIONWhat is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids?SUMMARY ANSWERUPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation.WHAT IS KNOWN ALREADYAdministration of all SPRM class members results in PAEC (progesterone receptor modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid receptor expression, progesterone (P)-regulated genes and cell proliferation are currently lacking.STUDY DESIGN SIZE, DURATIONObservational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9–12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38–52 with fibroids were derived from institutional tissue archives.PARTICIPANTS/MATERIALS, SETTING, METHODSStudy setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of progesterone (PR, PRB), androgen (AR), estrogen (ERα) receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67.MAIN RESULTS AND THE ROLE OF CHANCEUPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase samples. There were significant changes in pattern of expression of mRNAs encoded by IGFBP-1, FOXO1, IL-15, HAND2, IHH and HOXA10 compared with secretory phase samples consistent with low agonist activity in endometrium. Expression of mRNA encoded by FOXM1, a transcription factor implicated in cell cycle progression, was low in UPA-treated samples. Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared with those in the proliferative phase.LARGE SCALE DATAN/A.LIMITATIONS REASONS FOR CAUTIONA small number of well-characterized patients were studied in-depth. The impacts on morphology, molecular and cellular changes with SPRM, UPA administration on symptom control remains to be determined.WIDER IMPLICATIONS OF THE FINDINGSP plays a pivotal role in endometrial function. P-action is mediated through interaction with the PR. These data provide support for onward development of the SPRM class of compounds as effective long-term medical therapy for heavy menstrual bleeding.STUDY FUNDING/COMPETING INTEREST(S)H.O.D.C. received has clinical research support for laboratory consumables and staff from Bayer Pharma Ag and provides consultancy advice (no personal remuneration) for Bayer Pharma Ag, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.; A.R.W.W. has received consultancy payments from Bayer, Gedeon Richter, Preglem SA, HRA Pharma; L.H.R.W., A.A.M., R.M., G.S. and P.T.K.S. have no conflicts of interest. Study funded in part from each of: Medical Research Council (G1002033; G1100356/1; MR/N022556/1); National Health Institute for Health Research (12/206/520) and TENOVUS Scotland.

Safety of treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate

ABSTRACTIntroduction: During the last decade, there has been increased emphasis on the role of progesterone in the promotion of fibroid growth, as well as heightened interest in modulating progesterone pathways by use of selective progesterone receptor modulators (SPRMs). Among them, ulipristal acetate (UPA) has proved its efficacy in the management of symptomatic myomas by controlling bleeding and inducing amenorrhea, and reducing the size of myomas in the majority of cases.Areas covered: In this review, we summarize published scientific studies exploring evidence of the safety of SPRMs and particularly UPA, a drug approved for the management of symptomatic uterine fibroids. We focus essentially on endometrial changes induced by UPA, and also evaluate other safety outcomes.Expert opinion: Data from published reports of randomized controlled trials (RCTs) over 5 years have demonstrated that UPA does indeed induce endometrial changes (known as progesterone receptor modulator-associated endometrial changes), but they have been shown to be both benign and reversible.

A prospective, open-label, multicenter study to assess the pharmacodynamics and safety of repeated use of 30 mg ulipristal acetate

ObjectiveUlipristal acetate (UPA) 30mg is safe and effective for emergency contraception (EC). This prospective open-label exploratory study was conducted to obtain additional data on the pharmacodynamic effects of repeated dose of UPA 30mg during an 8-week period (effects on ovulation inhibition, hormonal levels, endometrium and cervical mucus). Safety and tolerability data of repeated use of UPA EC were also collected. Study designA total of 23 healthy female, healthy sterilized women participated in two substudies receiving UPA for 8 consecutive weeks. In substudy 1, UPA 30mg was administered every 7days (Q7D n=12); while in substudy 2, every 5days (Q5D n=11). Subjects were monitored three times a week in a baseline cycle and during treatment with transvaginal ultrasounds, hormonal measurements and cervical mucus evaluation. Laboratory safety measurements and standard surrogate thrombosis risk markers were measured at baseline and within a few days of the last tablet. A luteal phase endometrial biopsy was taken in the baseline cycle and posttreatment. ResultsA total of 11/12 (91.7%) and 8/11 (72.7%) of the subjects ovulated at least once in substudy Q7D and Q5D, respectively, with similar, normal hormonal profiles. No effect on cervical mucus was observed. All biopsies were classified as benign in both substudies; 5/11 biopsies on Q5D posttreatment were classified as nonphysiological with some of typical progesterone receptor modulator-associated endometrial changes. UPA was well tolerated in both treatment arms while clinical laboratory results and surrogate thrombosis markers were reassuring. ConclusionsRepeat use of 30mg oral UPA every 5 or 7days for 8weeks initially delays follicular rupture but ovulation eventually occurs with time in most subjects. Safety data indicate that UPA 30mg could be safely administered if needed more than once for EC in a given menstrual cycle. ImplicationsThese data demonstrate that repeated use of UPA 30mg is safe. However, ovulation eventually occurs in a high proportion of women in spite of repeated treatments in both studied regimens. Nevertheless, since the stage of follicular development of women seeking initial or repeat EC use is generally unknown, the repeated use of UPA may still delay follicular rupture and prevent an unintended pregnancy in the event of further unprotected intercourse.

A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception

ObjectiveTo determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles. Study DesignThis was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500 μg/day) or a high-dose (2500 μg/day) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns. ResultsAll subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12 weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding. ConclusionThe 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500-μg/day ring. ImplicationsThe 3-month CVR delivering UPA 2500 μg/day can become an effective user-controlled estrogen-free contraceptive method. Benign PAEC during treatment returns to normal after discontinuation. The prevention of occasional excessive withdrawal bleeding, either by a progestin or by using higher UPA levels to increase follicle suppression may permit prolonged treatment.

Selective progesterone receptor modulators.

Review of recent data from clinical trials and descriptions of endometrial morphology with administration of selective progesterone receptor modulators (SPRMs). Recent reports concerning administration of SPRMs, specifically the efficacy of ulipristal acetate in reducing fibroid size and rapid control of menstrual blood loss, have renewed clinical interest in this class of compound. Histological data from studies with SPRMs report that this class of drugs is associated with progesterone receptor modulator-associated endometrial changes. Data on mechanisms of action are lacking. The antagonistic progesterone effect of SPRMs has shown promising results in animal studies with endometriosis. Sex steroid receptor effects of PRMs outside the reproductive tract raise the potential for use in neurology and oncology, and although there are several randomized trials in these areas, there are limited small studies published to date. The SPRM ulipristal acetate is an effective treatment for preoperative treatment of fibroids and a reliable emergency contraceptive. This class of compounds holds the potential for long-term effective medical management of fibroids and may have utility in the management of other sex steroid-dependent conditions.

Individualized vaginal bleeding experience of women with uterine fibroids in the PEARL I randomized controlled trial comparing the effects of ulipristal acetate or placebo

What is the individualized bleeding experience of women with fibroids and anaemia in a 3 month randomized placebo controlled trial (PEARL I) of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA)? In contrast to continuing excessive regular menstruation in the placebo group, a majority of women treated with UPA (63.1% of those on 5 mg/day and 71.3% of those on 10 mg/day) experienced the rapid onset of amenorrhoea or minimal blood loss [pictorial blood loss assessment chart (PBAC) < 12]. The remainder experienced various patterns of bleeding and intensity of blood loss that are described for the first time, including an association of irregular bleeding on UPA with sub-mucous fibroids. The majority experience on UPA is amenorrhoea but the bleeding experience of the others has not been characterized. A 13 week randomized controlled trial in women, eligible for surgery for uterine fibroids and anaemia, comparing placebo (n = 48), UPA 5 mg (n = 95) or UPA 10 mg (n = 94). The treatment aim was fibroid shrinkage and the primary definitions and outcomes are published elsewhere; here the secondary outcome measure of vaginal bleeding pattern is described. Women, 18-50 years old, with fibroids and haemoglobin ≤10.2 g/dl, justifying surgery. At least one fibroid was 3-10 cm diameter and uterus ≤16 weeks pregnancy size. All used the daily PBAC methodology in a screening cycle (Ps) and throughout treatment, and for the 4 weeks preceding Week 26 and Week 38 in those who did not have surgery. An excessive menstruation is PBAC > 100. The bleeding patterns were characterized using the classification of Belsey, developed under auspices of WHO. In the placebo group, all women had an excessive screening PBAC [median 376; interquartile range (IQR) 241-574]; 81.3% of them had regular menstrual bleeding and the intensity of bleeding remained similar, so that the median PBAC in the next three periods was 90, 92 and 93% of the screening value. Four of the 48 women had spontaneous improvement in bleeding and one developed amenorrhoea and elevation of gonadotrophins. In the placebo group, 22 women provided Week 26 and 21 women provided Week 38 PBAC data. The median Week 26 PBAC (312: IQR 102-524) and Week 38 PBAC (236; IQR 103-465) indicated ongoing excessive bleeding. In the UPA group, screening PBAC confirmed excessive bleeding (UPA 5 mg, median 358; IQR 232-621; UPA 10 mg, median 330; IQR 235-542). UPA was initiated from the start of a menstruation (P1) and no women had regular periods on treatment. Following P1 through the whole of the remaining 13 weeks of UPA treatment amenorrhoea or minimal loss (PBAC < 12 for whole phase) occurred in 63.1% (UPA 5 mg) or 71.3% (UPA 10 mg). The characterization of the individualized bleeding experience of the remaining women on 5 mg and 10 mg UPA, respectively, were infrequent bleeding in 17.9 and 12.8%; frequent or prolonged bleeding or both in 12.7 and 11.7% and irregular bleeding in 5.3 and 3.2%. In those with prolonged, frequent or irregular bleeding there was a high chance that sub-mucous fibroids were present (UPA 5 mg 100% and UPA 10 mg 78.6%) but no correlation with progesterone receptor modulator-associated endometrial changes. The follow-up PBAC data at Week 26 and Week 38 are only valid for women who did not have surgical intervention. These groups may not be representative of the groups at screening. This first detailed description of these SPRM bleeding patterns provides clinicians with an indication of potential responses in women using the SPRM UPA and provides an extended definition of bleeding in untreated women with excessive bleeding and fibroids. Funded by PregLem/Gedeon Richter. D.H.B. is a member of the Scientific Advisory Board of PregLem, and in this role participated in the study design and supervision. Stock originally held in PregLem was given up when PregLem was incorporated into Gedeon Richter; D.H.B. does not currently hold stock. M.A.L. has received payment from Gideon Richter to attend a meeting to present these data (Barcelona, April 2013) but no financial support in preparing the manuscript. B.C.J.M.F. is a member of the Scientific Advisory Board of PregLem and has received fees and grant support from the following companies: Andromed, Ardana, Auxogyn, Ferring, Genovum, Gedeon Richter, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Roche, Schering, Schering Plough, Serono, Watson Laboratories and Wyeth. P.T. is a paid statistical consultant for PregLem SA. E.B. is a full time employee of PregLem and received payment from stocks sold in October 2010 from the company's full acquisition by Gedeon Richter Group. ClinicalTrials.gov Identifier: NCT00755755 (PEARL I).

Intérêt actuel des selective progesterone receptor modulators (SPRM) dans l’endométriose

The SPRM (selective progesterone receptor modulators) are agonists and/or antagonists of progesterone receptor. They are responsible for anovulation, amenorrhea and a lower prostaglandin levels, which leads to an improvement in pain and regression of lesions in endometriosis. On the endometrium, a particular aspect, the progesterone receptor modulator-associated endometrial changes (PAEC), raises additional studies to verify its harmlessness. However, due to the lack of hypoestrogenism and metabolic effects with these drugs, it is very likely that the SPRM will in the near future an important place in the treatment of endometriosis.