Uterine fibroids: management and reproductive considerations

Transcription

1 Uterine fibroids: management and reproductive considerations MM Dolmans, MD, PhD Université catholique de Louvain Institut de Recherche Expérimentale et Clinique Implications of myomas What are the mechanisms by which fertility could be impaired? Donnez J, Jadoul P. Hum Reprod Jun;17(6):

2 2 Causes Fibroids related infertility Uterine cavity distortion Endometrial and myometrial impaired blood supply Increased uterine contractibility Hormonal, paracrine and molecular changes (cytokines, NK, IL-10) Thicker capsule Gene expression ( HoxA 10) Neuropeptides Neurotransmitters Causes Fibroids related infertility Uterine cavity distortion Endometrial and myometrial impaired blood supply Increased uterine contractibility Hormonal, paracrine and molecular changes (cytokines, NK, IL-10) Thicker capsule Gene expression ( HoxA 10) Neuropeptides Neurotransmitters

3 3 Causes Fibroids related infertility Uterine cavity distortion Endometrial and myometrial impaired blood supply Increased uterine contractibility Hormonal, paracrine and molecular changes (cytokines, NK, IL-10) Thicker capsule Gene expression ( HoxA 10) Neuropeptides Neurotransmitters Causes Fibroids related infertility Uterine cavity distortion Endometrial and myometrial impaired blood supply Increased uterine contractibility Hormonal, paracrine and molecular changes (cytokines, NK, IL-10) Thicker capsule Gene expression ( HoxA 10) Neuropeptides Neurotransmitters

4 4 Causes Fibroids related infertility Uterine cavity distortion Endometrial and myometrial impaired blood supply Increased uterine contractibility Hormonal, paracrine and molecular changes (cytokines, NK, IL-10) Thicker capsule Gene expression ( HoxA 10) Neuropeptides Neurotransmitters Causes Fibroids related infertility Uterine cavity distortion Endometrial and myometrial impaired blood supply Increased uterine contractibility Hormonal, paracrine and molecular changes (cytokines, NK, IL-10) Thicker capsule Gene expression ( HoxA 10) Neuropeptides Neurotransmitters

5 Fibroid volume (cm 3 ) Baseline VI low Baseline VI high baseline 3 months 6 months 12 months Fibroid volume (cm 3 ) 180 Baseline volume low Baseline volume high High vascular index Low vascular index 20 0 baseline 3 months 6 months 12 months 40 Relationship between fibroid vascularisation and fibroid growth Vascular Index (VI) is the number of colour voxels divided by the total number of both colour and grey voxels, representing the proportion of blood vessels within the tissue Nieuwenhuis HK, et al. Br J Obstet Gynaecol Feb 17. doi: / [Epub ahead of print] Fibroids growth per year Fibroids have a median volume growth rate of 32.5% per year Small fibroids (<2 cm) grow significantly faster than larger fibroids Thompson M, Carr B. Int J Womens Health 2016 May;8:

6 Factors controlling fibroid growth Bulun S. N Engl J Med 2013;369: Walker CL, Stewart EA. Science 2005;308: Mechanism of action of GnRHa and SPRMs 6

7 New perspectives: Medical therapy of myomas To treat symptoms To prevent occurrence in women genetically predisposed to develop myomas Medical therapy of myomas To postpone or avoid surgery To prevent recurrence after surgery in women at high risk (young age, family history, etc) Around 40% of women with fibroids have significant symptoms HMB (Heavy menstrual bleeding) Mass effects (bulk symptoms) Infertility 7

8 To treat or not to treat? Management strategies for uterine fibroids Hysteroscopic myomectomy 8

9 Laparoscopic myomectomy Implications of surgical intervention in patients wishing to preserve their fertility 1. Risks Main risk: bleeding during surgery 2. Impact on uterine integrity Suture dehiscence Risk of rupture Intrauterine adhesions (in case of uterine cavity opening) 3. Implications for future fertility Postoperative adhesions Risk in case of repeat surgery 9

10 Hysteroscopic myomectomy Courtesy of Attilio Di Spiezio 10

11 Management strategies for uterine fibroids It should be emphasized that a desire for future pregnancy is a relative contraindication as the lack of published data means that a good pregnancy outcome cannot be ensured Although UAE is highly effective for treating symptoms (reduction in bleeding and fibroid size), the risk of reoperation is a reality: 15 20% after successful embolization and up to 50% in cases of incomplete infarction MRgFUS, magnetic resonance-guided focused surgery; UAE, uterine artery embolization Why we need new options Indeed, there are probably too many myomectomies in young ladies... provoking scars of the myometrium It is therefore necessary to develop and evaluate alternatives to surgical procedures, especially when fertility preservation is the goal 11

12 In 2002 What are the implications of myomas on fertility? A need for a debate? Donnez J, Jadoul P. Hum Reprod Jun;17(6): In years later! was the evidence any better? 12

13 Pregnancy outcomes and submucous fibroids Outcome Submucous fibroids RR (95% CI) P value Clinical pregnancy rate ( ) =0.005 Implantation rate ( ) =0.003 Ongoing pregnancy/lbr ( ) <0.022 Spontaneous abortion rate ( =0.022 *All studies LBR: live birth rate N.S. Not significant Pritts EA, Parker WH, Olive DL. Fertil Steril Apr;91(4): Fibroids and infertility: an updated systematic review of the evidence (Pritts,Parker and Olive, FS 2009) Fertility outcomes are decreased in women with submucosal fibroids, and removal seems to confer benefit. Subserosal fibroids do not affect fertility outcomes, and removal does not confer benefit. Intramural fibroids appear to decrease fertility, but the results of therapy are unclear. More high-quality studies need to be directed toward the value of myomectomy for intramural fibroids, focusing on issues such as size, number, and proximity to the endometrium. Pritts EA, Parker WH, Olive DL. Fertil Steril Apr;91(4):

14 Fibroids and infertility 2016 The need to treat submucosal fibroids is widely accepted, but fibroids in other locations and sizes continue to present a clinical conundrum Purohit P, Vigneswaran K. Curr Obstet Gynecol Rep. 2016;5:81 88 Management of Type 0 fibroids Management of Type 1 fibroids Adapted from Donnez J, and Dolmans MM, Hum Reprod Update Nov;22(6):

15 Fibroids and infertility The intramural fibroids To treat or not to treat? Fibroids and Infertility In years later! Is the evidence any better? 15

16 Infertility and myomas Effect of non-cavity distorting intramural fibroids on assisted reproduction outcomes: a cohort study Belen Marqueta, Pedro N. Barri, Buenaventura Coroleu, Pedro N. Barri Soldevilla, Ignacio Rodriguez 15 years later! Is the evidence any better? No...the literature remains confusing 16

17 Intramural myomas and infertility According to the literature,intramural myomas are the cause of infertility if... One myoma >5 cm (FIGO 2, 2-5, 3.) Two or three myomas >3/4 cm The real question? WHY NOT If there is a possible relationship between the size, the proximity to the endometrium and infertility, 17

18 The real question? WHY NOT If there is a possible relationship between the size, the proximity to the endometrium and infertility, why not try to reduce the myoma size and make it a completely non distorting myoma Goals of medical therapy should be 1)Reduce fibroid size 2)Change from a distorting to a non-distorting myoma At diagnosis (35 x 36 mm) After 3 months of SPRM (22 x 22 mm) 18

19 Type 2 myomas or multiple myomas (Type 2 5) or Type 2 5 with a desire for pregnancy Long-term intermittent UPA therapy (two courses of 3 months) Very good response (>50%) and restoration of the uterine cavity Good response (25 50%) Poor or insufficient response Try natural conception or IVF Try natural conception or IVF (if uterine cavity is restored) If the cavity remains distorted* Surgery (myomectomy) *If the myoma remains large due to great volume at baseline, surgery is still indicated Adapted from Donnez J, and Dolmans MM, Hum Reprod Update Nov;22(6): Efficacy: Fibroid volume reduction Median % change from screening Median change from screening in total fibroid volume a After Course 1* After Course 2* p< a Volume of three largest fibroids combined *After treatment course + 1 bleed ECM, extracellular matrix; UPA, ulipristal acetate ECM volume fraction (%) 100 ECM volume fraction in leiomyoma Two courses of 3 months significantly reduced ECM volume fraction *** p< *** *** *** Donnez J, et al. Fertil Steril Jan;105(1): Courtoy GE, et al. Fertil Steril Aug;104(2):

20 UPA treatment, two courses Type 2 myomas or multiple myomas (Type 2 5) or Type 2 5 with a desire for pregnancy Long-term intermittent UPA therapy (two courses of 3 months) Very good response (>50%) and restoration of the uterine cavity Good response (25 50%) Poor or insufficient response Try natural conception or IVF Try natural conception or IVF (if uterine cavity is restored) If the cavity remains distorted* Surgery (myomectomy) *If the myoma remains large due to great volume at baseline, surgery is still indicated Adapted from Donnez J, and Dolmans MM, Hum Reprod Update Nov;22(6):

21 Before treatment At the end of the treatment 30-year-old patient G0P0 Menorraghia Unclear desire regarding pregnancy MRI: multiple myomas At the end of the treatment, there was significant shrinkage Adapted from Luyckx M et al, Fertil Steril Nov;102: Spontaneous pregnancy 1 year after delivery No regrowth of fibroids during pregnancy and vaginal delivery No regrowth of fibroids after delivery 21

22 Type 2 myomas or multiple myomas (Type 2 5) or Type 2 5 with a desire for pregnancy Long-term intermittent UPA therapy (two courses of 3 months) Very good response (>50%) and restoration of the uterine cavity Good response (25 50%) Poor or insufficient response Try natural conception or IVF Try natural conception or IVF (if uterine cavity is restored) If the cavity remains distorted* Surgery (myomectomy) *If the myoma remains large due to great volume at baseline, surgery is still indicated Adapted from Donnez J, and Dolmans MM, Hum Reprod Update Nov;22(6): year-old woman Emergency room for menorrhagia Vaginal examination: uterus // 15W Hb: 9.3 g/dl The following day: 8.1 g/dl 22

23 Before treatment At the end of treatment (two courses of 3 months) Hb at the end of the treatment: 12.7 g/dl Accessible to laparoscopic and hysteroscopic myomectomy Spontaneous twin pregnancy in January 2013 Delivery by caesarean section Conclusions Infertility related to fibroids 1. Establish the relationship case by case, considering other causes of infertility 2. For uterine fibroids (FIGO 2), use medical therapy as first approach Uterine cavity restored Uterine cavity distorted *Before natural conception or IVF Natural conception IVF Surgical approach* 23

24 Thank you for your attention New perspectives: Medical therapy of myomas To treat symptoms To prevent occurrence in women genetically predisposed to developing myomas Medical therapy of myomas To postpone or avoid surgery To prevent recurrence after surgery in women at high risk (young age, family history, etc.) Adapted from Donnez J, et al. Hum Reprod Update Nov;22(6):

25 Women of reproductive age with Type 2 myomas or multiple myomas (Type 2 5), according to whether or not they have a desire for pregnancy Adapted from Donnez J, et al. Hum Reprod Update Nov;22(6): Mrs M 19-year-old patient (African) Emergency room for meno-metrorraghia Vaginal examination: uterus // W Hb: 7.4 g/dl MRI: multiple myomas 25

26 Received UPA + iron for 6 months (2008) Hb 11.9 g/dl after 6 months Large shrinkage of the submucous myomas and restoration of the uterine cavity Mrs M: Outcome of UPA treatment At the end of the treatment, no surgery was performed as the patient did not want to get pregnant and was free of symptoms Conclusions 1. If we had performed the surgery in 2007, the risk of repeated surgery was evaluated to be 50% at 5 years 2. As a result of UPA treatment, the surgery was postponed in this very young patient who had a high risk of recurrence due to genetic predisposition 26

27 The future: Expectant management or prevention? Medical therapy to prevent further growth? and possible infertility? Current management Woman of less than 20 years of age 5 small myomas (<12 mm), type 3 Asymptomatic 27

28 Intramural fibroids: To treat or not to treat? Fibroids have a median volume growth rate of 32.5% per year Small fibroids (<2 cm) grow significantly faster than larger fibroids Thompson M, Carr B. Int J Womens Health 2016 May;8: Let me end my lecture with a question: Should we take the risk of further growth or should we prevent this growth to preserve fertility? 28

29 Presentations of past cases where surgical intervention impacted fertility outcomes and/or compromised uterine integrity When should medical management be first-line treatment in patients wishing to preserve their fertility? 1. Distortion of the uterine cavity 2. Multiple myomas >3-4 cm in diameter 29

30 Presentations of successful cases with medical treatment for patients wishing to preserve their fertility Two scenarios 1. Excellent response no need for surgery 2. Significant fibroid reduction, but cavity still distorted surgery Further questions on fertility-related scenarios 1. Can we give 6 months of continuous therapy? Yes 2. When should we start stimulation (COS)? On the third day after the second menstrual bleed after end of treatment (EOT) 3. When should we initiate cryopreservation? Oocyte or mbryo freezing may be done before starting UPA and after COS, as described above 30

31 Concerning uterine adenomyosis and endometriosis? Adenomyosis T2 images Before treatment After 5mg UPA 3 months White arrow à Adenomyosis Blue arrow à Endometrial thickness 31

32 OBJECTIVE: To investigate the changes in the sonographically detectable alterations of the myometrium and pain symptoms caused by adenomyosis in patients treated with UPA because of uterine fibroids. DESIGN: Prospective open-label assessor-blind study. Women of reproductive age with adenomyosis and uterine fibroids 3-months oral UPA 5mg/day prior to laparoscopic or hysteroscopic treatment of uterine fibroids Ultrasonography (2D and 3D) before and after treatment Conclusions: In patients with adenomyosisand uterine fibroids, UPA causes a significant improvement in bleeding but it may worsen pain symptoms in more than half of the patients. This observation is justified by the worsening of several ultrasonographic characteristics of adenomyosis. Patients treated with UPA should be assessed for the presence of uterine adenomyosis 32

33 Concerning uterine adenomyosis and endometriosis? Endometriosis Endometriosis and fibroids are 2 completely different diseases even though they are both estrogen-dependant Endometriosis is characterised by progesterone resistance and uterine fibroids are influenced by progesterone Donnez J & Dolmans MM. Human Reproduct Update 2016, Jul 27. [Epub ahead of print] X 2.9 cm X 1.9 cm 3.6 cm 1.9 cm X, endometrioma Donnez J & Dolmans MM. Human Reproduct Update 2016, Jul 27. [Epub ahead of print] 33

34 Should hormonal IUDs be removed during UPA treatment? There are no data concerning the use of UPA in this scenario However, based on the mechanism of action of SPRMs (progestogen antagonist), we can expect that the presence of an IUD delivering levonorgestrel (e.g. Mirena ) would interfere with the effect of UPA IUD, intrauterine device; SPRM, selective progesterone receptor modulator UPA, ulipristal acetate 34

35 Can UPA be used for other bleeding problems (such as dysfunctional uterine bleeding)? This use is off-label However, some centers where UPA treatment has been used successfully to treat patients with dysfunctional uterine bleeding reported good results UPA, ulipristal acetate What are the effects of SPRMs on breast tissue? One in vitro study 1 In the mifepristone treated animals no tumours were palpable at 12 months of age One clinical trial 2 SPRM treatment with mifepristone in 30 otherwise healthy women with uterine fibroids had no negative effects in breast tissue; in fact, an antiproliferative effect on breast cells was observed SPRM, selective progesterone receptor modulator 1. Poole AJ, et al. Science 2006;314: Engman M, et al. Hum Reprod 2008;23:

36 Additional biochemical/molecular data on collagen deposition changes after the second course of treatment (short mention of this in the other lectures) to further reinforce its importance More MMP activity in long-term responsive myomas than in non-responsive samples Additional biochemical/molecular data on collagen deposition changes after the second course of treatment (short mention of this in the other lectures) to further reinforce its importance Less fibrosis after repeated courses of UPA, presumably thanks to MMPs 36

37 Impact of myomas on fertility When should medical management be first-line treatment in patients wishing to preserve their fertility? 1. Distortion of the uterine cavity 2. Multiple myomas >3-4 cm in diameter 37

38 Additional biochemical/molecular data on collagen deposition changes after the second course of treatment (short mention of this in the other lectures) to further reinforce its importance Less fibrosis after repeated courses of UPA, presumably thanks to MMPs No/modest response to UPA interms of fibroid volume reduction About 35% of low or no response after a single course, poor response in 25% after repeated courses 38

39 In case of no/modest response in terms of fibroid volume reduction 1. Increase in myoma volume failure surgery (unless bleeding is well controlled and the patient is happy) 2. No response (fibroid volume) Good bleeding control: continue Poor bleeding control (5%): STOP 3. Modest reduction after one course: continue for a second course as the impact could be more significant Some preliminary Asian data: Korean paper showing modest fibroid volume reduction after 1 course. Is the Asian population possibly less responsive? Bear in mind: 1. Volume reduction after 1 course is 30% (diameter) 2. Vaginal ultrasound evaluation of myomas is not straightforward, particularly in case of multiple myomas A number of epigenetic changes could explain some racial differences in pathways (receptors, MMP2, survivin, etc ) 39

40 Some preliminary Asian data: Korean paper showing modest fibroid volume reduction after 1 course. Hence the question Is the Asian population possibly less responsive? Presurgical use of Esmya modification of the surgical technique (video) Softer myoma consistency due to collagen degradation (MMP2 collagenase) Incidence: 5% to 15% Double «anchorage» Intracapsular dissection 40

41 Can we administer 2 6-months courses continuously in patients wishing to preserve their fertility, to shorten waiting times prior to IVF? Yes At the end of 6 month s therapy, endometrial thickness should be evaluated on the third day of the second menstrual bleed If OK, COS may be initiated When should we freeze eggs/embryos in patients on Esmya? What is the recommended IVF regimen for patients undergoing Esmya treatment? 1. No IVF during Esmya therapy COS to be started the third day of the second menstruation after EOT 2. Always possible to freeze oocytes/embryos before UPA treatment (surely indicated in patients >35y) 41

42 Can we freeze eggs during off-treatment periods? No available data Benefits are limited in any case, as we only save 3 months What is the success rate of implantation in women wishing to preserve their fertility after Esmya treatment? It depends on the extent of restoration of the uterine cavity and global uterine volume reduction 42

43 Myomectomy vs medical treatment in patients wishing to preserve their fertility: what are the key considerations? Uterine cavity distortion (type 0, I, II) Presence of intramural myomas >4 cm Women of advanced child-bearing age with fibroids but still wishing to conceive will have to wait almost a year (2 courses and a further 2 menses) for IVF treatment. Medical therapy for one year implies a further decline in oocyte quality/reserve decreasing fertility potential even more (opportunity cost). How do we manage the cost benefits of medical treatment for such patients prior to IVF, as medical therapy takes a long time and does not guarantee fibroid resolution. In this case, I strongly recommend stimulating 2-3 cycles (depending on the <36y vs >36y) before UPA therapy in order to obtain oocytes (for vitrification) Then, 6 months of continuous therapy UPA Then, thawing and embryo transfer after the second menstrual bleed post-eot, if the uterine cavity is no longer distorted 43

44 Regarding the paper on treatment algorithms, what about type 6 and 7 uterine fibroids? Would you recommend oral medical treatment for these fibroids? Type 6: depending on size Diameter Surgery Type 7: surgery if symptomatic Fibroid management has always been surgical, enabling us to confirm that the fibroids are non-cancerous. A long-term medical approach could potentially lead to late diagnosis of cancerous fibroids and, if so, how should we mitigate this? First remark: incidence of leiomyosarcomas is <0.3% Moreover, this question is valid for All medical therapeutic options All alternatives (UAE, MRgFUS, cryotherapy, thermocoagulation, etc ) 44

45 Some patients want to deal with their fibroids as soon as possible, and sometimes there is a need to do so. Are there any data on short-term GnRHa administration (1-2 months) to swiftly shrink the fibroids first, followed by long-term Esmya use to maintain and sustain fibroid reduction? Swiftly shrink the fibroids first: no evidence that GnRHa is able to achieve this (flare-up) Maintain and sustain: no data Note that the mode of action is different For patients with irregular periods, is it necessary to induce menses to initiate treatment? Can we still implement treatment by adhering to the 3-month course, 2-month interval principle in terms of duration? 1. Irregular menses: Endometrial thickness evaluation Endometrial biopsy 2. If biopsy excludes atypical hyperplasia or AC, it is recommended that menses be induced by 10 days of NETA 10 mg, starting UPA onthe second or third day of bleeding 45

46 How do published data stack up between the PEARL trials in Europe, American (VENUS) studies and Asian data from Korean patients? 1. The VENUS program in the USA considered mostly African-American women (approx 70%), unlike the PEARL trials (less than 10%). Women of African origin have a higher prevalence of uterine fibroids, and their genetic make-up highlights potential differences in the severity of the disease and response to treatment. Moreover, the USA population involved women with a higher BMI (32 vs 24), which may also point to differences in these populations. 2. Selection criteria for VENUS patients used alkaline hematin vs the PBAC score as screening methods. The primary efficacy endpoint (amenorrhea) in VENUS was defined as an absence of bleeding in the last 35 days of treatment, while PEARL considered ANY 35 consecutive days, hence the results are not comparable. A new sub-analysis to homologate both endpoints will be performed by Allergan 3. VENUS studies did not standardize measurements of fibroids, hence volume results are not conclusive. One additional phase III trial (VENUS III) is planned to address the volume issue. 4. Epigenetic changes may also explain differences between African-Americans and the African population living in Europe. Indeed, the black women living in Belgium respond very well. The difference between the USA and the EU is that African-American women are descendants of several generations that have lived in the USA for centuries. African women have only lived in Belgium for 50 years. Certain epigenetic changes could welle be responsible for enzyme or gene modifications. What is the rate of recurrence or, in the absence of data, the possibility of fibroid regrowth after Esmya treatment of 2 courses? 50% in case of a moderate response Very low in «excellent» responders Data from PREMYA study provide further insights 46

47 It is clear that Esmya can be used for uterine fibroids in case of different patient profiles. Are there any patient profiles/cases where Esmya should not be used? Why do around 20% of patients not respond to treatment intended to reduce for fibroid volume? RT-qPCR array results: Poor or non-responsive myomas express higher levels of CTNND2 (Catenin-δ2) Catenin-δ2 promotes the Wnt pathway, which stimulates proliferation of myoma progenitor cells, but unresponsive myomas might escape the effect because of higher Wnt signaling activity 47

48 Role of survivin (BIRC5), an apoptosis inhibitor RT-qPCR array results: Responsive short-term express lower levels of Survivin Lowersurvivin levelsfacilitate apoptosis Responsive short-term express lower levelsof survivin Apoptosisoccurs essentiallyduring the first course of treatment (Courtoy et al, 2015) Role of survivin (BIRC5), an apoptosis inhibitor, in short-term responsive myomas Caspase-8, -10 Caspase-9 Survivin Caspase-3, -7 Apoptosis Bax 48

49 MMP regulation by TNF-α / TGF-β signaling Even after 2 treatment courses, fibroid reduction looks modest on ultrasound in some patients, but symptom control is very good. Is it possible that Asian patients may require >2 courses, since fibroid shrinkage is progressive? Yes There are surely epigenetic factors explaining some differences in the pathway 49

50 PCOS and diabetic patients are known to be at greater risk of endometrial hyperplasia. Is it safe for these patients, especially perimenopausal women, to undergo long-term medical treatment (4 courses or more)? Safety measures: Endometrial thickness evaluation Endometrial biopsy (if >6 mm on day 3) In case of endometrial hyperplasia (non-atypical): NETA (10 mg) for 10 days and initiation of UPA therapy(after induced bleeding) The benefits of Esmya for correction of anaemia and symptomatic control of bleeding prior to surgery are clear. After taking Esmya, what is your experience as to whether Esmyais beneficial for bleeding control during surgery? No data In my experience, no difference 50

51 How will presurgical use of Esmya impact subsequent surgical techniques for fibroids in terms ofplane of cleavage, softness, and so on? Are there data advocating use of Esmya in patients with both fibroids and adenomyosis? Fibroids and moderateendometriosis: OK In case of very severe adenomyosis: no response with UPA 51

52 ClinicoEconomics and Outcomes Research 2017: EurJ ObstetGynecol Reprod Biol Jul 8;216:

53 Expert Opin Drug Saf Dec;15(12): DOI: /

54 Murji et al. Cochrane Database SystRev Apr 26;4:CD doi: / CD pub2 J. Bateman, et al., Histomorphological changes in endometriosis in a patient treated with ulipristal: A case report, Pathol. Res. Pract (2016), 54

55 The patients must be informed of the contraceptive options if flexible interval therapy with UPA is to be undertaken. T. Römer et al. Symptomatischer Uterus myomatosus Zielgerichtete medikamentöse Therapie, FRAUENARZT 58 (2017) Nr. 6, Seite , 55

56 Safrai et al. Obstet Gynecol 2017;0:1 4 In conclusion, selective progesterone receptor modulators offer an important treatment option for a large group of women. Although symptomatic leiomyomas have a major effect on the quality of life of many women, until recently, available medical therapies were all associated with major side effects rendering them unsuitable for long-term treatment. The risks and benefits for each treatment option need to be presented to the patient enabling her to reach an informed decision with proper coordination of expectations. The new agents provide optimism in our attempt to improve patients quality of life with the understanding that for the time being, surgical therapy remains the only definitive treatment. Whitaker et al. Human Reproduction, pp. 1 13,

57 Fauser BCJM, Donnez J, Bouchard P,Barlow DH, VaÂzquez F, Arriagada P, et al. (2017) Safety after extended repeated use of ulipristalacetate for uterine fibroids. PLoS ONE 12(3): e doi: /journal.pone Seitz et al, Contemporary Clinical Trials /j.cct

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62 Presurgical use of Esmya modification of the surgical technique (video) Softer myoma consistency due to collagen degradation (MMP2 collagenase) Incidence: 5% to 15% Double «anchorage» Intracapsular dissection 62

63 Can we administer 2 6-months courses continuously in patients wishing to preserve their fertility, to shorten waiting times prior to IVF? Yes At the end of 6 month s therapy, endometrial thickness should be evaluated on the third day of the second menstrual bleed If OK, COS may be initiated When should we freeze eggs/embryos in patients on Esmya? What is the recommended IVF regimen for patients undergoing Esmya treatment? 1. No IVF during Esmya therapy COS to be started the third day of the second menstruation after EOT 2. Always possible to freeze oocytes/embryos before UPA treatment (surely indicated in patients >35y) 63

64 Can we freeze eggs during off-treatment periods? No available data Benefits are limited in any case, as we only save 3 months What is the success rate of implantation in women wishing to preserve their fertility after Esmya treatment? It depends on the extent of restoration of the uterine cavity and global uterine volume reduction 64

65 Myomectomy vs medical treatment in patients wishing to preserve their fertility: what are the key considerations? Uterine cavity distortion (type 0, I, II) Presence of intramural myomas >4 cm Women of advanced child-bearing age with fibroids but still wishing to conceive will have to wait almost a year (2 courses and a further 2 menses) for IVF treatment. Medical therapy for one year implies a further decline in oocyte quality/reserve decreasing fertility potential even more (opportunity cost). How do we manage the cost benefits of medical treatment for such patients prior to IVF, as medical therapy takes a long time and does not guarantee fibroid resolution. In this case, I strongly recommend stimulating 2-3 cycles (depending on the <36y vs >36y) before UPA therapy in order to obtain oocytes (for vitrification) Then, 6 months of continuous therapy UPA Then, thawing and embryo transfer after the second menstrual bleed post-eot, if the uterine cavity is no longer distorted 65

66 Regarding the paper on treatment algorithms, what about type 6 and 7 uterine fibroids? Would you recommend oral medical treatment for these fibroids? Type 6: depending on size Diameter Surgery Type 7: surgery if symptomatic Fibroid management has always been surgical, enabling us to confirm that the fibroids are non-cancerous. A long-term medical approach could potentially lead to late diagnosis of cancerous fibroids and, if so, how should we mitigate this? First remark: incidence <0.3% Moreover, this question is valid for All medical therapeutic options All alternatives (UAE, MRgFUS, cryotherapy, thermocoagulation, etc ) 66

67 Some patients want to deal with their fibroids as soon as possible, and sometimes there is a need to do so. Are there any data on short-term GnRHa administration (1-2 months) to swiftly shrink the fibroids first, followed by long-term Esmya use to maintain and sustain fibroid reduction? Swiftly shrink the fibroids first: no evidence that GnRHa is able to achieve this (flare-up) Maintain and sustain: no data Note that the mode of action is different For patients with irregular periods, is it necessary to induce menses to initiate treatment? Can we still implement treatment by adhering to the 3-month course, 2-month interval principle in terms of duration? 1. Irregular menses: Endometrial thickness evaluation Endometrial biopsy 2. If biopsy excludes atypical hyperplasia or AC, it is recommended that menses be induced by 10 days of NETA 10 mg, starting UPA onthe second or third day of bleeding 67

68 How do published data stack up between the PEARL trials in Europe, American (VENUS) studies and Asian data from Korean patients? 1. The VENUS program in the USA considered mostly African-American women (approx 70%), unlike the PEARL trials (less than 10%). Women of African origin have a higher prevalence of uterine fibroids, and their genetic make-up highlights potential differences in the severity of the disease and response to treatment. Moreover, the USA population involved women with a higher BMI (32 vs 24), which may also point to differences in these populations. 2. Selection criteria for VENUS patients used alkaline hematin vs the PBAC score as screening methods. The primary efficacy endpoint (amenorrhea) in VENUS was defined as an absence of bleeding in the last 35 days of treatment, while PEARL considered ANY 35 consecutive days, hence the results are not comparable. A new sub-analysis to homologate both endpoints will be performed by Allergan 3. VENUS studies did not standardize measurements of fibroids, hence volume results are not conclusive. One additional phase III trial (VENUS III) is planned to address the volume issue. 4. Epigenetic changes may also explain differences between African-Americans and the African population living in Europe. Indeed, the black women living in Belgium respond very well. The difference between the USA and the EU is that African-American women are descendants of several generations that have lived in the USA for centuries. African women have only lived in Belgium for 50 years. Certain epigenetic changes could well be responsible for enzyme or gene modifications. What is the rate of recurrence or, in the absence of data, the possibility of fibroid regrowth after Esmya treatment of 2 courses? 50% in case of a moderate response Very low in «excellent» responders Data from PREMYA study provide further insights 68

69 It is clear that Esmya can be used for uterine fibroids in case of different patient profiles. Are there any patient profiles/cases where Esmya should not be used? Why do around 20% of patients not respond to treatment intended to reduce for fibroid volume? RT-qPCR array results: Poor or non-responsive myomas express higher levels of CTNND2 (Catenin-δ2) Catenin-δ2 promotes the Wnt pathway, which stimulates proliferation of myoma progenitor cells, but unresponsive myomas might escape the effect because of higher Wnt signaling activity 69

70 Role of survivin (BIRC5), an apoptosis inhibitor RT-qPCR array results: Responsive short-term express lower levels of Survivin Lowersurvivin levelsfacilitate apoptosis Responsive short-term express lower levelsof survivin Apoptosisoccurs essentiallyduring the first course of treatment (Courtoy et al, 2015) Role of survivin (BIRC5), an apoptosis inhibitor, in short-term responsive myomas Caspase-8, -10 Caspase-9 Survivin Caspase-3, -7 Apoptosis Bax 70

71 Even after 2 treatment courses, fibroid reduction looks modest on ultrasound in some patients, but symptom control is very good. Is it possible that Asian patients may require >2 courses, since fibroid shrinkage is progressive? Yes There are surely epigenetic factors explaining some differences in the pathway PCOS and diabetic patients are known to be at greater risk of endometrial hyperplasia. Is it safe for these patients, especially perimenopausal women, to undergo long-term medical treatment (4 courses or more)? Safety measures: Endometrial thickness evaluation Endometrial biopsy (if >6 mm on day 3) In case of endometrial hyperplasia (non-atypical): NETA (10 mg) for 10 days and initiation of UPA therapy(after induced bleeding) 71

72 The benefits of Esmya for correction of anaemia and symptomatic control of bleeding prior to surgery are clear. After taking Esmya, what is your experience as to whether Esmyais beneficial for bleeding control during surgery? No data In my experience, no difference How will presurgical use of Esmya impact subsequent surgical techniques for fibroids in terms ofplane of cleavage, softness, and so on? 72

73 Are there data advocating use of Esmya in patients with both fibroids and adenomyosis? Fibroids and moderateendometriosis: OK In case of very severe adenomyosis: no response with UPA Seitz et al, Contemporary Clinical Trials /j.cct

74 Management of uterine fibroids in women with otherwise unexplained infertility Recommendation: There is fair evidence to recommend against myomectomy in women with intramural fibroids (hysteroscopically confirmed intact endometrium) and otherwise unexplained infertility, regardless of their size. (II-2D) If the patient has no other options, the benefits of myomectomy should be weighed against the risks, and management of intramural fibroids should be individualised. (III-C) Carranza-Mamane B, et al. J Obstet Gynaecol Can Mar;37(3): Back up Separation slide(back up) 74

75 Association of uterine fibroids and pregnancy outcomes after ovarian stimulation-intrauterine insemination for unexplained infertility No differences were observed in conception and live birth rates in women with non-cavitydistorting fibroids and those without fibroids. These findings provide reassurance that pregnancy success is not impacted in couples with non-cavity-distorting fibroids undergoing OS-IUI for unexplained infertility Styer AK. Fertil Steril Mar;107(3): Decrease in fibroid volume and vascular indices after 3 months of ulipristal acetate therapy Influence of ulipristal acetate therapy compared with uterine artery embolization on fibroid volume and vascularity indices assessed by three-dimensional ultrasound: prospective observational study Czuczwar P, et al. Ultrasound Obstet Gynecol Jun;45(6):

76 Main findings: Baseline fibroid vascularisation measured using three-dimensional Doppler was significantly related to fibroid volume at 12 months and fibroid growth rate as a % of volume at baseline over 1 year. Fibroid volume increase was larger in highly vascularised fibroids (also after correction for baseline fibroid volume and other confounders). Vascular Index of fibroid capsule at baseline was not related to fibroid volume at 12 months Nieuwenhuis HK, et al. Br J Obstet Gynaecol Feb 17. doi: / [Epub ahead of print] Type 2 myomas or multiple myomas (Type 2 5) or Type 2 5 with a desire for pregnancy Long-term intermittent UPA therapy (two courses of 3 months) Very good response (>50%) and restoration of the uterine cavity Good response (25 50%) Poor or insufficient response Try natural conception or IVF Try natural conception or IVF (if uterine cavity is restored) If the cavity remains distorted* Surgery (myomectomy) *If the myoma remains large due to great volume at baseline, surgery is still indicated Adapted from Donnez J, et al. Hum Reprod Update Nov;22(6):

77 Around 40% of women with fibroids have significant symptoms HMB (heavy menstrual bleeding) Mass effects (bulk symptoms) Infertility Uterine fibroid (UF) pseudocapsule Different entity from fibroid No correlation between capsule and fibroid vascularisation No correlation between capsule vascularisation and fibroid growth 77

78 Structure of the UF pseudocapsule Fibro-neurovascular bundle created by the uterus during the development and growth of the UF Similar to normal myometrium Malvasi A, et al. Eur J Obstet Gynecol Reprod Biol Jun;162(2): Limitations Large uterine vessels were not evaluated Group of patients relatively asymptomatic since they did not have any medical or surgical treatment over the 12 months of follow-up 78

79 Why we need new options 1. It is necessary to develop and evaluate alternatives to surgical procedures, especially when fertility preservation is the goal But limitations Secondary analysis of a series of 900 couples with unexplained infertility 11.3% of participants had at least documented fibroids and normal cavities 79

80 New perspectives: Medical therapy of myomas To treat symptoms To prevent occurrence in women genetically predisposed to developing myomas Medical therapy of myomas To postpone or avoid surgery To prevent recurrence after surgery in women at high risk (young age, family history, etc.) Adapted from Donnez J, et al. Hum Reprod Update Nov;22(6): Efficacy: Fibroid volume reduction Median change from screening in total fibroid volume a Median % change from screening After Course 1* p<0.001 After Course 2* After Course 3* After Course 4* Follow-Up N=207 N=189 N=173 N=160 N=158 UPA 5 mg a Volume of three largest fibroids combined *After treatment course + 1 bleed Donnez J, et al. Fertil Steril Jan;105(1):

81 Infertility and myomas: Conclusions Yan et al.: although non-cavity-distorting fibroids do not affect IVF/ICSI outcomes, intramural fibroids >2.85 cm in size significantly impair the delivery rate of patients undergoing IVF/ICSI Donnez et al.: Myomas distorting the uterine cavity and non-cavity-distorting intramural myomas >4 cm in diameter could impair fertility Marqueta et al.: non-cavity-distorting intramural fibroids have a detrimental effect on live births, clinical pregnancy, implantation and delivery rates in patients undergoing ART Yan L, et al. Fertil Steril Mar;101(3): Donnez et al. Fertil Steril 2014 Marqueta B, et al. J Endometr Pelvic Pain Disord. 2016;8: