Fibroid growth and medical options for treatment Nathalie Chabbert-Buffet, M.D., Ph.D.,a Nathalie Esber, M.Sc.,b,c and Philippe Bouchard, M.D.d,e a Obstetrics, Gynecology and Reproductive Medicine Department, AP-HP, Hospital Tenon, Paris; b INSERM, U693, Le  de Me  decine Paris-Sud, Le Kremlin-Bice ^tre; d Univ Paris-Sud, UMR-S693, Le Kremlin-Bice ^ tre; ^tre; c Faculte Kremlin-Bice and e UPMC Paris 06, Paris, France

Although fibroids are common benign tumors, their impact on women's quality of life can be considerable. The most frequent symptoms are uterine bleeding, resulting in anemia, and pelvic pain. Fibroids can be of genetic or hormonal origin or arise from intrauterine events. Current options for medical treatment include control of estradiol and progesterone production or action and are discussed in this review. Although curative treatment of fibroids relies on surgical strategies, the current trend is for uterine-sparing treatment to preserve fertility and avoid unnecessary surgery. Currently approved medical treatments include intrauterine progestin delivery to reduce uterine bleeding, GnRH analogues, and, more recently, selective progesterone receptor modulators to control uterine bleeding and reduce fibroid volume. (Fertil SterilÒ 2014;102: Use your smartphone 630–9. Ó2014 by American Society for Reproductive Medicine.) to scan this QR code Key Words: Fibroids, sex steroids, fibroids treatment, progestins, selective progesterone and connect to the receptor modulators, selective estrogen receptor modulators Discuss: You can discuss this article with its authors and other ASRM members at http:// fertstertforum.com/chabbertbuffetn-fibroids-growth-medical-treatment/

F

ibroids are the most common gynecologic tumors, occurring in
70% of women over 30 years of age (1). They are benign tumors developing in the myometrium. Despite the high incidence of the disease and its impact on women's quality of life, there has been relatively little research on fibroids until recently (2). Fibroids develop from a single myometrial smooth muscle cell and are therefore classified as a clonal disease (3, 4). Risk factors for developing fibroids, apart from ethnic origin and heredity, include situations causing prolonged high exposure to estrogens and/or progesterone, such as early age of menarche (5, 6), polycystic ovary syndrome (7), obesity (8), and late pregnancy (9). Consistent with these epidemiologic data, the best known stimulator of tumor

growth is the combined action of estrogens and progesterone. Growth factors, cytokines, and chemokines (1) have also been described as playing a role. Several animal and in vitro models (5) developed over the past decade have contributed to a better understanding of the disease. Fibroids are mostly asymptomatic (80%) but can induce symptoms with a high impact on women's health (10) depending on their size and location. Until recently, they were largely classified as being either subserosal or interstitial. However, the International Federation of Gynecology and Obstetrics now recognizse eight subtypes: types 0–2, submucosal; 3–5, interstitial; 5–7, subserosal; and 8, extrauterine (e.g., parametrium; Fig. 1) (11). Heavy menstrual bleeding is the most frequent fibroid-related symptom, re-

Received June 9, 2014; revised and accepted July 15, 2014. N.C.-B. is a member of the French Gedeon Richter's scientific advisory board. N.E. is funded by HRA Pharma for her Ph.D. P.B. is a member of Preglem's scientific advisory board. Reprint requests: Nathalie Chabbert-Buffet, M.D., Ph.D., Obstetrics Gynecology and Reproductive Medicine Department, Tenon Hospital, 4 rue de la Chine, 75 020 Paris, France (E-mail: [email protected]). Fertility and Sterility® Vol. 102, No. 3, September 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.07.1238 630

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sulting in reduced quality of life and anemia (5), and it can be related either to the location of the fibroid (submucosal) or to fibroid-related endometrial dysfunction (11). In addition, associated endometrial lesions may be present in up to 20% women with abnormal uterine bleeding, particularly adenomyosis (12–15). Pretherapeutic workup should, of course, aim to identify these associated conditions, because they may require specific care. Symptoms related to tumor volume are less frequent and include pelvic pain, dyspareunia, and urinary symptoms, such as pollakiuria and dysuria. Fibroid volume can also occasionally result in urinary tract compression and ureteral dilation, which can lead to renal dysfunction. The role of fibroids in infertility is limited and mostly related to submucosal lesions resulting in implantation defects (16). Whether large interstitial fibroids can cause infertility through deformation of the uterine cavity is still under discussion (16). However, although African women have a high incidence of fibroids and more severe lesions, their rate of fertility remains high even VOL. 102 NO. 3 / SEPTEMBER 2014

Fertility and Sterility®

FIGURE 1

The 2011 FIGO classification of fibroids (reproduced from Munro et al. [11] with permission). Chabbert-Buffet. Fibroids growth and treatment. Fertil Steril 2014.

though pregnancy usually occurs at an age where the rate of fibroids is already high: 25–35 years (17). Although bleeding may have a marked impact on their quality of life, women often delay seeking medical advice. This may be because they underestimate the importance of the bleeding (18) or because of a fear of surgical treatment. It is therefore important that women are better informed about medical treatment options. The only curative treatment to date is surgical removal either by myomectomy or hysterectomy. Although alternative surgical strategies have resulted in a reduction of the number of hysterectomies (19), 55,000 hysterectomies a year are still performed for fibroids in the United Kingdom and 600,000 in the United States (20), resulting in a heavy economic burden (21). Destruction techniques, by ultrasound or radiofrequency (22), are under evaluation as complementary or associated techniques. Endometrial ablation, either by surgical or physical means, such as thermablation (23), is an alternative option for women close to menopause who would like to avoid surgery (20). However, the current trend is for uterine-sparing therapeutic strategies, mainly because the age of a first pregnancy is on the increase. Because myomectomy can be detrimental on pregnancy outcome (24), medical options are frequently offered as a first-line option. Medical therapy is also required before surgery in women with fibroid-related anemia to reduce postoperative morbidity (25) or to facilitate endometrial ablation techniques (26). Most medical treatments reduce bleeding. Modulators of estrogen signaling, such as aromatase inhibitors, and selective estrogen receptor modulators (SERMs) have been evaluated. Progestins are also used for this purpose but have limited efficacy and can induce tumor growth as discussed below. Finally GnRH analogues and selective progesterone receptor modulators (SPRMs) can be used to reduce both tumor volume and bleeding (Table 1).

FIBROID GROWTH Although quite a lot is known about the factors contributing to fibroid growth, the pathophysiology of this disease remains largely unelucidated (1, 5). VOL. 102 NO. 3 / SEPTEMBER 2014

Histology Fibroids are benign tumors developing in the myometrium (Fig. 2) and appear as a disordered organization of the myometrial cells forming spheres and nesting in abundant extracellular matrix (ECM) (9, 27). This results in the classic surgical description of fibroids as firm tumors with a clear dissection plane and easy to enucleate. Other histologic presentations have been described, such as cellular fibroids with scarce ECM component or bizarre fibroids with unusual, but nonsuspect, tissue organization. Numerous other forms have also been described (9), including vascular fibroids, intravascular fibroids, and benign disseminating fibroids (leiomyomatosis) (28). These latter forms, though benign, can be life-threatening. Preoperative differential diagnosis with sarcoma is mostly based on the analysis of the tumor vascularization on Doppler-coupled ultrasound scan and magnetic resonance imaging (29). This differential diagnosis is important, especially in the case of a nonsurgical therapeutic option, even though sarcomas are extremely rare, occurring in
10 out of 1 million women every year (30). Stem cells may be involved in fibroid growth. Specific myometrial cellular subpopulations exhibiting myometrial stem cell characteristics have been identified (31) and found to be necessary for fibroid growth in an animal model (32). These cells appear to be pluripotent and may be tumor initiating (33). One single stem cell is thought to give birth to a specific fibroid (which is why it is called a clonal disease) (3, 4). Stem cells present in fibroids, compared with stem cells in normal myometrium, carry mutations of the MED12 (mediator complex subunit 12) gene located on the X chromosome (32). This suggests a primary role of genetic events in the stem cells to allow tumor growth. MED12 is one of the components involved in the control of transcription initiation in association with the preinitiation complex (34). Finally, the role of the ECM in fibroid growth, as part of the tumor microenvironment, is also thought to be very

FIGURE 2

Fibroid growth. CCR ¼ complex chromosomal rearrangement; ECM ¼ extracellular matrix; ER ¼ estrogen receptor; PR ¼ progesterone receptor. Chabbert-Buffet. Fibroids growth and treatment. Fertil Steril 2014.

631

VIEWS AND REVIEWS

TABLE 1 Fibroid treatment: hormone production and signalling modulators. Therapeutic class Progestins GnRH analogues SPRMs

Molecules Danazol DMPA LNG-IUS Leuprorelin acetate Mifepristone Ulipristal acetate Asoprisnil Telapristone acetate

Aromatase inhibitors SERMs

Raloxifene

Therapeutic effects in women with fibroids Bleeding control Bleeding control, tumor volume reduction Rapid bleeding control Tumor volume control Bleeding control Tumor volume control Tumor volume control; limited data Questionable efficacy

Main adverse events Fibroid growth Weight gain Expulsion Hot flushes, bone demineralization PAECs

Status

FDA approval FDA approval FDA approval

Reference(s) (87) (26, 149) (88) (90) (150) (10, 75, 121)

Phase II Hot flushes, joint pain

Phase II

(102)

Hot flushes, DVT

Phase II

(100)

Note: DMPA ¼ depot medroxyprogesterone acetate; DVT ¼ deep vein thrombosis; LNG-IUS ¼ levonorgestrel-delivering intrauterine system; PAECs ¼ progesterone receptor modulator–associated endometrial changes; SERMs ¼ selective estrogen receptor modulators; SPRMs ¼ selective progesterone receptor modulators. Chabbert-Buffet. Fibroids growth and treatment. Fertil Steril 2014.

important. As previously described, an increase in tumor volume can be related to cell proliferation (cellular fibroids, bizarre fibroids) or ECM accumulation (usual fibroids). ECM in fibroids is abnormal in structure and physical properties (35) compared with the normal myometrial ECM. Previous nonhuman animal models have shown discrepancies between human and nonhuman pathophysiology, because tumors in other animals do not include excess ECM (5). Important discrepancies have also been observed between cellular models of fibroids, without ECM, and in vivo experiments. The role of ECM has been confirmed in a recently developed model of human fibroid xenograft in immunodeficient mice (36). Tumor growth control by sex steroids in a paracrine system of regulation has also been described (37). Estradiol appears to be necessary to allow the progesterone stimulatory action on fibroid growth as discussed below. In addition, E2 and P action seems to be necessary for the production of ECM components, such as collagen types I and II. In fact collagen fibers are overexpressed in the follicular phase of the cycle (38) and the P receptor antagonist asoprisnil down-regulates collagen fiber synthesis in an in vitro model (39).

Genetics Apart from the very rare syndromic fibroids associated with aggressive renal cancer in individuals with fumarate hydratase (FH) gene mutations on chromosome 1 (40), the genetic component of fibroids remains speculative. Studies into somatic genetic alterations revealed that 50% of fibroids have chromosomal abnormalities. Genetic alterations have been described in 12 out of 26 chromosomes, and nine main candidate genes have been identified: MED12, HMGA2, HMGA1, FH, BHD, TSC2, PCOLCE, ORC5L, and LHFPL3 (1, 9). In addition to somatic gene alterations, epigenetic mechanisms also may be involved independently from specific modifications of the DNA sequence. Differences in DNA methylation, involved in gene transcription repression, have been described in fibroids compared with the normal surrounding myometrium (41). Most of these DNA methylation 632

modifications occur in the promoter region of the involved genes, including a number of tumor repressors, such as KLF11, a P receptor target gene. These modifications result in silencing the corresponding genes in fibroids, therefore promoting tumor growth. Other epigenetic modifications may include histone modifications, which modulate gene transcription, and microRNAs which modulate protein production downstream of gene transcription. Data on histone modifications are extremely limited to date (42). Data regarding microRNA (43, 44) show that several microRNAs are deregulated in fibroids, as well as their target genes. More recently, a whole-genome sequencing study of fibroids from 30 patients (45) has provided complementary information. It was shown that identical variants may be identified in different nodules—up to five different nodules from the same patient—suggesting a common cellular origin. Single mutations have been observed mostly in MED12 and FH genes. Modifications at chromosome 7q locus were frequent, particularly the COL4A5–COL4A6 locus, as well as modifications of the HMGA2 locus on chromosome 12 and RAD51B on chromosome 14. Complex chromosomal rearrangements (CCRs) in fibroids were also observed, sharing common features with chromothripsis, a single-genomic event that results in focal losses and rearrangements in multiple genomic regions. This leads to cell death and apoptosis, but is also involved in carcinogenesis. In fibroids, chromothripsis-like events appear to lead to benign tumor development. None of the samples studied carried TP53 mutations, confirming benignity. CCRs are most probably due to multiple chromosomal breaks and random reassembly, and they promote tumor growth.

Risk Factors for Fibroids The epidemiology of fibroids suggests two distinct patterns depending on ethnic background (46). In women of African origin, fibroids occur early in their reproductive life, they are more often numerous and larger in size, recurrence occurs more often, and they do not regress after menopause (47). Other VOL. 102 NO. 3 / SEPTEMBER 2014

Fertility and Sterility® risk factors identified in this population (7, 48–52) include age, early menarche, overweight, and polycystic ovary syndrome. Tumoral molecular biology studies suggest that E2 metabolism may be altered in women of African origin, because polymorphism in the catecholamine-O-methyl transferase (COMT) gene leading to reduced enzyme activity has been correlated with increased tumor size (53). However, this polymorphism does not appear to alter fibroid prevalence (54). The product of E2 transformation by COMT, 2-methoxyE2, has been shown to be involved in the regulation of aromatase activity and estrogen signaling in fibroids. In women of European origin (46), fibroids are most frequent in women in their 40s, suggesting an important role of the duration of exposure to sex steroids (55). Fibroids regress after menopause, suggesting that tissue aging alone is not a sufficient mechanism. Obesity is a major risk factor, and adiponectin (56, 57), a cytokine secreted by the adipose tissue, may be involved as well. Endocrine disruptors may also play a role. Environmental exposure to phthalates (58) is associated with fibroid development, as well as with endometriosis. Intrauterine exposure to diethylstilbestrol (59) also has been related to an increased risk of developing fibroids. The number and size of fibroids vary considerably from one woman to another.

Role of Sex Steroids Data from in vitro and nonhuman animal models over the years suggest that E2 plays a central role in fibroid growth via its receptor, ERa. Fibroid cells cultured in vitro and treated with estrogens proliferate. In mouse (60) and guinea pig (61) models, exogenous E2 has been shown to promote tumor growth (37). Estradiol from the general circulation as well as locally produced (62) is involved. This is supported mostly by clinical data showing that aromatase inhibitors are as effective as GnRH analogues in reducing fibroid volume in premenopausal women, with circulating E2 levels remaining normal to high in aromatase inhibitor users and low in GnRH analogue users (63). Estradiol therefore acts via its a receptor (64). However, while high levels of ERa/ERb mRNA have been described in fibroids compared with normal adjacent myometrium (65) subsequent analysis of the corresponding protein expression failed to confirm that overexpression or unbalanced expression of ER isoforms plays a potential specific role (66). Initial data on the action of P were more controversial (37). Depending on the experimental conditions, progestins were found to stimulate or inhibit cell proliferation in in vitro models. In a mouse model, P was able to inhibit estrogeninducing tumor growth (36). In the Eker rat model (67) P was unable to stimulate tumor growth whereas estrogens could. In parallel, clinical data suggested a major role of P in fibroid growth. Proliferation markers are overexpressed in fibroids during the luteal phase (68), as well as in postmenopausal women treated with estrogens and progestins, but not with estrogens only (69). In postmenopausal women, the stimulatory effect of hormone replacement therapy on fibroid growth has been correlated with the progestin dose (70). Whereas treatment with GnRH analogues results in fibroid shrinkage, VOL. 102 NO. 3 / SEPTEMBER 2014

cotreatment with progestins limited their therapeutic efficacy (71). This was not observed in women cotreated with estrogens and progestins (72). Finally, recent clinical studies have shown that four different SPRMs cause fibroids to shrink (73, 74) in the efficacy range of GnRH analogues (75). This effect was observed despite maintained E2 levels (75) and brings further evidence of the role of the P receptor (PR) and its ligand in fibroid growth. In fibroids, P acts through its nuclear receptor as well as other nonnuclear signaling systems. The nuclear PR exists as two main isoforms (PRA and PRB) arising from the same gene (76). Interestingly, the ratio of the two isoforms appears to be balanced in fibroids as well as in the adjacent myometrium (77). This is in contrast with data from other proliferating benign or malignant diseases, such as endometriosis or breast cancer, where an unbalanced PRA/ PRB ratio is involved in tumor growth (78, 79). Progesterone may also signal through membrane proteins (80), which have not been evaluated in fibroids. Recently a truncated form of the nuclear PR, deleted of its DNA-binding region and localized to the mitochondria (PR-M), has been cloned. An increase in PR-M expression has been observed in fibroids and may be involved in fibroid growth through altered mitochondrial activity and cellular respiration (81). Biologic actions of the ligand-PR complex have been evaluated in genome-wide PR binding experiments (1). Ligand-receptor interaction induces PR binding to a very high number of distinct sites over the genome and activation of multiple gene transcription. Further research is needed to correlate these complex events with the role of genetic events discussed above or with therapeutic effects. Finally, in the fibroid xenograft mouse model (36) in which both fibroids and the microenvironment can be evaluated, it has been shown that P and E2 together, but not administered alone, cause cell proliferation and ECM accumulation. This synergistic effect was reverted by the SPRM mifepristone. Taken together, these data suggest that both E2 and P, and their specific receptors ERa, PRA, and PRB, are involved in fibroid growth. Both steroids appear to act in a collaborative system where E2 allows the expression of PRs which in turn control cell proliferation and ECM production. However, although fibroid growth appears to depend on sex steroids, ERs and PRs are not expressed in all tumor cells, suggesting paracrine mechanisms. In particular, stem cells express extremely low levels of sex steroid receptors (32). In vitro data suggest that coculture with fibroid cells allow stem cells to grow into large tumors when grafted to immunodeficient mice (32). Other components of the tumor microenvironment, including adipocytes, may exert paracrine regulation through growth factors, cytokines, and chemokines (56, 82–86).

FIBROID TREATMENT For years the only curative treatment for fibroids was considered to be surgery, but alternate options are available today. Although hysterectomy remains the first treatment option for fibroids, women are increasingly choosing to avoid hysterectomy either because they are approaching menopause or because they want to preserve pregnancy opportunities. 633

VIEWS AND REVIEWS Other options include: limited surgery, i.e., myomectomy either by hysteroscopy, laparoscopy, or laparotomy for some cases (depending on the number, size and type of tumor); embolization of fibroids; and physical destruction by ultrasound and radiofrequency, which is currently under evaluation. Medical treatment is initially used to relieve heavy menstrual bleeding. It improves a woman's quality of life, relieves anemia-related symptoms, and reduces subsequent surgical morbidity. In addition, medical treatment reducing the uterine volume can facilitate surgical management. It is important to note that all medical treatment options to date induce anovulation or are contraindicated in pregnant women and, therefore, in women wishing to conceive.

Progestins Oral or intramuscular progestins may be used to treat dysfunctional uterine bleeding associated with fibroids by reducing endometrial hyperplasia (Table 1). However, data from the literature are limited (87, 88) and tumor volume reduction has not been confirmed (89). This is probably the consequence of the multiple effects of progestins. Some of these are beneficial, such as endometrial atrophy or their effect in suppressing gonadotropin secretion. However, as already discussed, progestins such as P are growth factors for fibroids. Endometrial thinning before hysteroscopic surgery can be obtained with the use of danazol (26, 90, 91), although GnRH analogues have been shown to be more effective. Intrauterine delivery of progestins by means of an intrauterine system (IUS) is also an option (92). The levonorgestrelreleasing IUS (LNG-IUS) has been approved by the United States Food and Drug Administration to treat heavy menstrual bleeding in IUS users. In women with fibroid-related uterine bleeding, the LNG-IUS has been shown to reduce bleeding and improve anemia (88, 93). However, tumor volume was not reduced. In addition, insertion of an IUS can be difficult in women with submucosal fibroids, and the device can be expelled more frequently (94). However, the use of LNG-IUS may reduce the rate of hysterectomy and improve patient satisfaction (93).

Selective Estrogen Receptor Modulators SERMs are nonsteroidal estrogen receptor ligands with agonist or antagonist effects depending on the tissue. In contrast to tamoxifen, the widely used SERM in breast cancer, raloxifene exerts antiestrogenic effects in fibroids. Raloxifene reduces cell proliferation (95–98) and has no endometrial agonist activity (99). Three randomized controlled trials have evaluated raloxifene in premenopausal women with confirmed fibroids (Table 1) (100). Two of these trials, including 215 women, showed therapeutic efficacy of raloxifene, but the third did not. This may be due to the rise in E2 secretion observed in premenopausal women following SERM treatment. Clinical efficacy of raloxifene is therefore considered to be limited. Furthermore, tamoxifen does not appear to be suitable, owing to its agonistic effect in the endometrium (101). 634

Aromatase Inhibitors Aromatase is a cytochrome P450 enzyme (CYP-19) that allows the transformation of androgens into estrogens. Aromatase inhibitors are steroidal (exemestane) or nonsteroidal (anastrozole, letrozole) compounds that interact with the hormone-binding site of the molecule (exemestane) or with its catalytic subunit (anastrozole, letrozole). In premenopausal women, their use results in a rise in plasma E2 levels, so they are unlikely to be suitable to treat fibroids. However, they may contribute to a local decrease in E2 production within fibroids, as has been previously discussed (63). A single clinical trial has been included in a recent Cochrane data base review (Table 1) (102). This trial compared the aromatase inhibitor letrozole to the GnRH analogue triptorelin. It showed that letrozole reduces fibroid volumes by 46% (vs. 32% in the GnRH analogue group). However, no significant data are available regarding their impact on uterine bleeding, even though pilot studies have suggested that aromatase inhibitors may help to control uterine bleeding (103). To date, clinical data are too limited to allow aromatase inhibitors to be used for fibroid treatment in clinical practice.

GnRH Analogues GnRH analogues are synthetic peptidic compounds structurally close to the natural GnRH molecule. After binding to the GnRH receptors, agonistic analogues induce subsequent stimulation of gonadotropin secretion followed by desensitization, and thus they delay the gonadotropic axis blockade. In contrast, GnRH antagonists induce immediate blockade of GnRH receptors and immediate decrease in LH and FSH secretion. As a consequence, both E2 and P levels reach postmenopausal levels. This property has been used to treat fibroids, in part because of the ability of GnRH analogues to induce amenorrhea. In line with the already discussed pathophysiology, additional biologic effects related to low E2 and P levels have been described. In addition to their effects on circulating steroid levels, GnRH analogues have been shown to decrease different paracrine mitogenic and angiogenic factor expression, such as vascular endothelial growth factor, fibroblastic growth factor, and plateletderived growth factor (104, 105). In vitro GnRH analogues inhibit cell proliferation and induce apoptosis (106). Studies of surgical samples of fibroids have contributed to understanding some of the pathways involved in apoptosis activation, such as down-regulation of the PI3 kinase protein kinase B pathway (107). Clinical randomized studies have shown that GnRH analogues can control bleeding, thus correcting anemia, and reduce fibroid volume by
50%. Surgical procedures are subsequently facilitated (Table 1) (90). Treatments with GnRH analogues have been evaluated, either alone or with an add-back therapy to limit their side effects, particularly the consequences of low estrogen secretion, such as hot flushes and a decrease in bone density. Add-back treatments include progestins, estrogen and progestin combinations, and raloxifene (91). However, the use of progestins as an add-back therapy appears to reduce the effect of GnRH analogues on fibroid volume. Alternatively, raloxifene treatment may VOL. 102 NO. 3 / SEPTEMBER 2014

Fertility and Sterility® help further reduce fibroid volume but is unable to decrease the intensity and frequency of hot flushes. Finally, the use of GnRH analogues results in fibroid shrinkage, but for a limited period corresponding to the duration of treatment, and E2 suppression (75). Fibroid volume increases after cessation of treatment, and mean changes from screening at week 38 (25 weeks, or 6 months, after treatment discontinuation) were 16.5% in the leuprorelin-treated group compared with 44.8% and 54.8% in the 5 mg/d and 10 mg/d ulipristal acetate (UPA)–treated groups, respectively, in the PEARL II study (75).

Selective Progesterone Receptor Modulators SPRMs are PR ligands with agonist, antagonist, or mixed activity depending on the cellular and molecular context (108). In vitro, cultured fibroid cells treated with the SPRM UPA, telapristone acetate, or asoprisnil showed a decrease in cell proliferation as well as an induction of apoptosis pathways (109–114). In contrast, these agents have no effect on the proliferation or apoptosis of normal myometrial cells. Asoprisnil and UPA also down-regulate a number of growth factors and their receptors in vitro (115, 116). Finally, asoprisnil and UPA can reduce ECM production in cultured fibroid cells by up-regulating ECM metalloproteinase activity in vitro (39, 110). Recently, looking for a molecular explanation, and potentially for a predictive marker of SPRM efficacy, Engman et al. suggested that the enzyme glutathione-S transferase mu 1 overexpression is associated with a significant response to treatment (117). A number of clinical trials have investigated the efficacy and safety of SPRMs as a treatment for fibroids, showing that mifepristone (118–120), UPA (74, 75, 118–121), asoprisnil (122, 123), and telapristone acetate (73) are all effective in reducing fibroid and uterine volume (73). Fibroid volumes are reduced by 17%–57% and uterine volume by 9%–53% following treatment with SPRMs compared with placebo (74). In contrast to GnRH agonist therapy, the SPRMs control tumor volume (75) for a prolonged period of up to 6 months after treatment discontinuation (75, 124). SPRMs are also able to suppress bleeding more rapidly than GnRH analogues in women with fibroids. In a randomized trial, bleeding control occurred within 7 days in a UPA group compared with 21 days in a leuprorelin group (74). Most women treated with UPA, asoprisnil, or mifepristone experience amenorrhea during the entire treatment (75, 123, 125). Importantly, bleeding control after treatment with an SPRM is not associated with signs of E2 deprivation, and E2 plasma levels are maintained at
60 pg/mL. In contrast, GnRH analogues induce postmenopausal levels of E2 and cause subsequent hot flushes and bone loss (75). All studies with SPRMs have reported an improvement in quality of life scales in subjects treated with UPA, asoprisnil, or mifepristone (126–130). UPA administered for 3 months at a daily dose of 5 mg is currently used in clinical practice to treat fibroids in the preoperative period in women eligible for surgical treatment. The recently published PEARL III study and its extension (121) resulted in the approval of the extension of treatment to VOL. 102 NO. 3 / SEPTEMBER 2014

a second course of 3 months in Europe. In that study, women received an initial 3-month course of 10 mg/d UPA. They could then be enrolled in the extension phase of the study where they were randomized to receive norethisterone acetate (NETA) or placebo for 10 days. A subsequent 3-month treatment with UPA was then started on the 4th day of bleeding, followed by a 10-days NETA/placebo period, up to a final of four courses of UPA. The study showed that amenorrhea was obtained after a mean of 3.5 days in the first UPA treatment period, and 2–3 days in subsequent courses. Ninety percent of women were amenorheic after the first course and 93%–94% of them had spotting or no bleeding at all in the subsequent courses. Fibroid volume reduction reached 45% after the first course and continued to decrease in subsequent treatment rounds to 72% after the fourth treatment course. We are currently awaiting further data from the Pearl IV study exploring long-term administration of UPA at 5 mg/d versus 10 mg/d (in 500 women) in Europe and from the Premya phase IV study also conducted in Europe.

Endometrium Changes There has been some concern regarding endometrial changes induced by medium- to long-term (3–6 months) continuous daily dosing of mifepristone (2–200 mg/d) (131) and asoprisnil (132, 133). Nonphysiologic endometrial changes characterized by dilated weakly secretory endometrial glands with few mitotic figures, and stromal effects ranging from compaction to nonuniform edema have been described. A panel of expert pathologists concluded that no safety concerns arise from these changes, which have been termed ‘‘progesterone receptor modulator–associated endometrial changes’’ (PAECs) (134, 135). Additional data from the PEARL I, II, and III studies (74, 75, 121) confirmed that PAECs were not a matter of concern. Endometrial thickening >16 mm occurred in 10%–12% of women, and endometrial histologic samples revealed no atypia, either simple or complex, in the treated groups (136). PAECs always disappear after treatment cessation (74, 75, 121). Administration of a progestin (121) after UPA discontinuation does not speed up regression of PAECs. However, data on PAECs require further evaluation, because this aspect has also been observed in women not receiving SPRMs. Screening of endometrial samples showed that 10% of women with fibroids had PAECs before administration of SPRMs (121).

Other Potential Therapeutic Options A number of potential treatments for fibroids are currently in preclinical or phase II studies (9). Additional studies are needed in women suffering from fibroids, particularly in women planning to conceive. Herbal therapy is being investigated in phase II clinical trials. For example, epigallocatechin gallate, found in green tea, has been shown to inhibit fibroid cell proliferation and induce apoptosis in vitro and in nonhuman animal models (137, 138). Inhibitors of fibrosis formation, such as pirfenidone (139), also have been evaluated. 635

VIEWS AND REVIEWS Correction of vitamin D deficiency, a common condition in northern countries, may be an important issue as well. Decreased vitamin D level has been described as a risk factor for developing fibroids (relative risk 2.4) (140), and sufficient vitamin D levels (>20 mg/mL) are associated with a decreased risk of developing fibroids independently from ethnic origin (odds ratio 0.68, 95% confidence interval 0.48–0.96) (141). In vitro, vitamin D reduces ECM production (142–144) and cellular proliferation in fibroid cells as well as in normal myometrial cells (145). In the Eker rat model, vitamin D causes fibroid shrinkage (146). In addition, the impact on bone mineral density of GnRH analogues used for fibroid treatment may be limited, or even reverted, by vitamin D supplementation (147, 148). Finally, molecules that control fibroid cell proliferation in vitro or in vivo may deserve clinical evaluation in the future. Growth factor receptor antagonists, such as AG1478 and TKS050, which block EGF signalling, or SB525334, which is a transforming growth factor beta signaling blocker, have been shown to control fibroid cell proliferation in vitro (9). Peroxisome proliferator–activated receptor gamma receptor ligands, such as roziglitazone and ciglitizone, also have been evaluated in vitro and shown to reduce fibroid cell proliferation (9).

CONCLUSION SPRMs appear to be the best therapy for women with symptomatic fibroids who prefer not to undergo surgery, especially when administered after a long-term discontinuous pattern (121). They may facilitate surgical procedures pending the review analysis of worldwide surgical experience. Apart from providing an option for women who wish to preserve childbearing potential, they may also be advantageous for women in their late 40s to delay invasive procedures until menopause, when the fibroids could regress naturally. This new therapeutic option appears to be safe and contributes to a rapid improvement of quality of life in women suffering from fibroids. We think that in the future, SPRMs may be combined with other more recent therapeutic options, such as growth factor modulators.

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