How can we best manage our patients Endometriosis hh.pptx

How can we best manage our patients Endometriosis

1. How can we best manage our patients Endometriosis for the long term ? An Overview from SEUD congress 2018

2. Manifestasi klinis Nyeri Pelvis Infertilitas Massa di Pelvis Perdarahan haid

3. 6 years Symptoms start First consultation 1 year Diagnosis Average delay ~ 7 years 1,2 1. Nnoaham KE et al . Fertil Steril 2011; 96(2): 366–373. 2. Arruda MS et al. Hum Reprod 2003; 18: 756–759. Significant diagnostic delay in endometriosis

4. Management of endometriosis MANAGEMENT Medical surgery

5. Management of endometriosis No permanent cure for endometriosis Aims of treatment (patient-dependent): Alleviate pain and other symptoms Reduce lesions Maintain/restore fertility Avoid recurrence Improve quality of life 6

6. The current approach Endometriosis diagnosis Immediate 1st surgery Medical treatment Repetitive surgeries ART

7. personal approach Endometriosis-related infertility modern management : Is an individualized treatment The gold standard Chapron, 2018

8. Individualization of Therapy No single approach ideal for all patients Tailor therapy to needs and choices of patient 1 Objective of individualized therapy: Manage complaint (pain/infertility) Optimize balance of efficacy, safety and tolerability profiles Enhance adherence 9 Kennedy S, Berggvist A, Chapron C et al. Hum Reprod 2005.

9. Treatment Approach Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2008. 10 ‘Endometriosis should be viewed as a chronic disease that requires a life-long management plan with the goal of maximizing the use of medical treatment and avoiding repeated surgical procedures’

10. P ersonal approach Diagnosis of endometriosis should no longer be considered as synonymous of immediate surgery Chapron (2018)

11. Surgical Therapy Aimed at removing endometrial implants and restoring fertility Efficacy reflects the skill of the surgeon Recurrence is common: 40–50% at 5 years 1,2 12 Mounsey AL, Wilgus A, Slawson DC. Am Fam Phys 2006; Guo SW. Hum Reprod Update 2009.

12. Personal approach Endometriosis : How to avoid unnecessary surgeries Indications for medical treatment First line option for pain (excepted desire for pregnancy) Real recurences after adequate 1st surgery Post – operatively to avoid recurrences ART as 1st line option for infertility followed by medical Ttt Existence of an associated adenomyosis To plan the best moment for surgery

13. P ersonal approach New strategy for endometriosis management (1) : To decrease The number of Unnecessary surgeries OMA ART Chapron, 2018 Few P ain Adenomyosis

14. New strategy for endometriosis management (2): To avoid Poorly Performed surgeries Endometriosis diagnosis Questioning Imaging preoperative work-up TVUS TRUS MRI SUP OMA DIE Adosis Endometriosis phenotype P ersonal approach

15. New strategy for endometriosis management (3): To plan the best moment To perform the surgery Once only in <<The endometriosis life >> P ersonal approach

16. P ersonal approach Surgery must be performed when the patient want to be pregnant Chapron, 2018

17. Severity of disease Clasisfication grade 3-4 Normogram : history and symptom Symptom : dyszhezia,dyspareunia,dysuria . Sign : immobility of uterus rectovaginal nodule Blood test : Ca 125 > 65  predict severity of endometriosis USG sign : question mark and sliding sign Coexistence with adenomiosis ,DIE and OMA

18. Klasifikasi Endometriosis dengan Laparoskopi ( rASRM / rAFS * Score ) 19 Revised American Society for Reproductive Medicine. Fertil Steril 1997. * rASRM , revised American Society for Reproductive Medicine * rAFS : revised American Fertility Society .

19. Normogram

20. Prevalensi dan Overlap pain 21 Hanya Dismenore 12.7% Nyeri pelvis + dismenore 25.2% Hanya nyeri pelvis 6.5% Nyeri pelvis + disparenia 3.3% Disparenia + nyeri pelvis + dismenore 34.4% Dismenore + disparenia 6.5% Hanya disparenia 0.7% Sinaii N, Plumb K, Cotton L et al. Fertil Steril 2008. 10.7% wanita tidak melaporkan gejala nyeri ginekologis

21. Endometriosis : mechanisms of pain I N F L A M M A T I ON Tissue Damage ONGOING PERIPHERAL ACTIVITY Nerve damage CENTRAL SENSITIZATION (Spinal, supraspinal and cortical) Symptoms Hyperalgesia Allodynia Spontaneous pain Decreased Threshold to Peripheral stimuli Expansion of Receptive field Increased Spontaneous activity

22. Surgery and Endometriosis Previous history OR 95% Laparotomy 3.64 1.08 - 12.31 Cesarean section 2.16 1.31 - 3.55 Liu et al., Reprod Sci (2016)

23. QUESTION MARK SIGN IS SEEN WITH DEP ENDO. Figure 1: Question mark sign How to Evaluate Adenomyosis in Patients Affected by Endometriosis? Nadine Di Donato and Renato Seracchioli Minimally Invasive Gynaecological Surgery Unit, S. Orsola-Malpight Hospital, University of Bologna, Via Massarenti 13, 40138 Bologna, Italy Correspondence should be addressed to Nadine Di Donato : [email protected]

24. ADD IN SLIDING SIGN…

25. DIE, Deep infiltrating endometriosis; OMA, Endometrioma 1. Lazerri L et al. Reprod Sci 2014; 21(8): 1027-1033

26. Personal approach << Endometriosis life >> Chapron, (2018) Endometriosis clinical diagnosis Long term Medical treatment ART Long term Medical treatment Unique and appropriate surgery Desire for pregnancy

27. Personal approach << Endometriosis life >> Chapron, (2018) Endometriosis clinical diagnosis Long term Medical treatment ART Long term Medical treatment Complete Appropriate Unique surgery Desire for pregnancy

28. Endometriosis : No infertility nor desire for pregnancy No pelvic pain : Asymptomatic endometriosis +++ No OMA OMA Expectant management Medical Ttt Fertility Preservation? Follow-up : Questioning Clinical examination TV US Pelvic pain Chapron, (2018) Long term +++ Medical Treatment 1st line : P, DNG and/or COC 2nd line : GnRHa Success Failure Success Post op Medical Ttt Surgery : Complete exeresis Medical Ttt first rather than Repetitive surgery Real recurrence Fertility Preservation ?

29. Medical Therapy 30 Specific therapies – approved in endometriosis e.g. gonadotropin-releasing hormone agonists, danazol and some progestins Non-specific therapies – not approved in endometriosis Including non-steroidal anti-inflammatory drugs and combined oral contraceptives

30. P ersonal approach It is possible to begin Medical treatment without previous histological confirmation Chapron (2018)

31. Endometriosis and Oral Contraceptives Previous OC use SUP* OMAs* DIE* NO Reference Reference Reference YES To treat severe 1st DM Other indications * Ad OR 95% Cl Chapron et al., Hum Reprod (2011) 3.5 (0.9- 13.5) 2.8 (1.1- 7.1) 1.9 (0.8- 4.3) 1.3 (0.8- 2.1) 16.2 (7.8- 35.3) 6.4 (3.2- 13.7)

32. Endometriosis and Oral Contraceptives OC users Ad OR 95 % Cl p Never user Reference Ever user 2.17 (1.19 – 3.95) p = 0.002 Current user 1.22 (0.6 – 2.52) p = NS Past user 2.79 (1.74 – 5.12) P = 0.002 Chapron et al., Hum Reprod (2011)

33. An ideal hormonal therapy for endometriosis should be able to AMELIORATE PAIN avoiding a hypoestrogenic state, with the further goal of restoring fertility , limited side effects , administered for prolonged period of time and less expensive Eur J Obstet Gynecol Reprod Biol . 2017 Feb;209:61-66

34. Vercellini , P. et al. Nat . Rev. Endocrinol . 10, 261–275 ( 2014 ) “Overall, medical therapy with ORAL CONTRACEPTIVES and PROGESTINS enables satisfactory long-term pain control in around two thirds of symptomatic women . The remaining third may benefit from conservative or definitive surgery, according to the desire to conceive” [email protected]

35. “… endometriosis is a chronic and incurable disease in a significant number of women. The treatments… can offer (partial) relief of pain symptoms, but symptoms often recur after discontinuation of therapy” ESHRE Endometriosis Guideline (Sept 2013) Dunselman et al. Human Reproduction 2014; 29:400–412 “Endometriosis is viewed best primarily as a medical disease with surgical back-up” “Multiple surgical procedures should be avoided whenever possible , because surgery has inherent risks and also might result in adhesions that can cause pelvic pain” Treatment of pelvic pain associated with endometriosis The Practice Committee of the American Society for Reproductive Medicine. Fertility and Sterility 2008; 90:S260–269 Why need long term management of endometriosis

36. 1. Park SY et al., Clin Exp Reprod Med. 2016; 43: 215–220. 2. Dunselman et al. Human Reproduction 2014; 29:400–412. 3. Ouchi N et al. J Obstet Gynaecol Res 2014;40:230–236. 4. Soliman AM et al. J Manag Care Spec Pharm, 2016;22(5):573–587 . 5. Sagsveen M et al., Cochrane Database Syst Rev. 2003;(4):CD001297. 6. Angioni S et al. Gynecol Endocrinol 2015;31:406–408 Prevent recurrence Alleviate pain 1 Avoid bone mineral loss Improve quality of life 6 Maintain treatment adherence 4 Preserve fertility 2 Key considerations in the long-term management of endometriosis

37. Expert Opin. Drug Saf. ( 2016 ) 15(1):21-30 PROGESTINS are increasingly and successfully employed as monotherapy for endometriosis, and because they do not increase the thrombotic risk , their use can be safely suggested in many women with contraindications to estrogens as well as in those who do not tolerate estrogens . [email protected]

38. Fertil Steril 2017;107:533–6 Based on controlled trial data, it appears that women with suspected or confirmed endometriosis as MAY DO BETTER with oral progestin-only treatment the first-line therapy because progestins have demonstrated benefits in reducing pain and suppressing the anatomic extent of endometriotic lesions . Fertil Steril 2017 ;107:533–6 can be used at any age do not increase the risk of thrombosis inhibit ovulation induce amenorrhea with very few side effects Oral P rogestins A lone

39. Fertil Steril 2017;107:533–6 Progestins inhibit ovulation and induce amenorrhea . The decrease in GN secretion induced centrally by progestins will result in a relatively hypoestrogenic state that could help suppress endometriosis and certainly should prevent progression of the disease Progestins have been shown to have anti- inflammatory and antiangiogenic activity Progestins also may decrease expression of matrix metalloproteinases (MMP), thereby decreasing the invasiveness of endometriosis implants Fertil Steril 2017 ;107:533–6

40. Guidelines for Progestins ESHRE guideline: Progestins ‘…can be considered as a first choice for the treatment of endometriosis because they are as effective in reducing [laparoscopy] scores and pain as danazol or GnRH agonists, and have a lower cost and a lower incidence of adverse effects’ 1 Other expert comment: ‘Given their good tolerability, minor metabolic effects and low cost, progestogens must therefore be considered the drugs of choice’ 2 41 GnRH, gonadotropin-releasing hormone ESRHE guideline. http://guidelines.endometriosis.org/pain.html. 2007; Vercellini P, Fedele L, Pietropaolo G et al. Hum Reprod Update 2003.

41. Biological Activities of Progesterone and Selected Progestins 42 Schindler AE, Campagnoli C, Druckmann R et al. Maturitas 2003. Key: + relevant activity; (+) activity not clinically relevant; – no activity. MPA, medroxyprogesterone acetate; NETA, norethisterone acetate Progestogenic activity Glucocorticoid activity Androgenic activity Anti-androgenic activity Anti-mineralocorticoid activity Progesterone + – – (+) + Dienogest + – – + – Drospirenone + – – + + Levonorgestrel + – + – – Gestodene + – (+) – (+) MPA + + + – – Norgestimate + – (+) – – NETA + – (+) – – Desogestrel + – (+) – – Cyproterone acetate + (+) – + –

42. Dienogest (DNG ) Dienogest also directly suppresses the gene expression of aromatase , a key enzyme in estrogen production Sacco K, et al. Gynecol Endocrinol 2012;28(2):134–138 Shimizu Y, et al. Steroids 2011;76(1-2):60–67 Yamanaka K, et al. Fertil Steril 2012;97(2):477–482 Dienogest ’ s inhibitory action on PGE2 and aromatase production in human endometrial epithelial cells may contribute to the therapeutic effect of Dienogest on the progression of endometriosis Regulatory approval for treating ENDOMETRIOSIS Dienogest inhibits the expression of key genes involved in PGE2 synthesis

43. Lazzeri L et al. Journal of Endometriosis, 2010 Antiangiogenic Effect -  VEGF e NGF Antinflammatory Effect -  PGs Dienogest  CELL PROLIFERATION  BLEEDING Immunomodulatory Effect -  TNF α PAIN

44. Europe Pain relief 2 Increased quality of life 1 Dienogest: long-term efficacy 1. Harada M et al . Gynecol Endocrinol 2011; 27(9): 717–720. 2. P etraglia F et al. Arch Gynecol Obstet. 2012; 285(1):167–73. Japan

45. Terapi Jangka panjang pasca operasi

46. Ota et al . 2015: long-term dienogest experience over 5 years fo recurrence prevention after endometrioma surgery

47. Pil Kontrasepsi kombinasi untuk dysmenorrhea

48. Dienogest Vs GnRH agonis pasca pembedahan 49

49. Dienogest Vs GnRH agonis pasca pembedahan 50

50. The evidence supporting Dienogest 2 mg as a long-term treatment option Can medical therapy be used for long-term management of endometriosis?

51. Dienogest 2mg : Limitations and side effects of other hormonal Ttts Specific properties Well tolerated and efficient for endometriosis Efficiency in cases of associated adenomyosis (30%)

52. Dienogest 2mg : Dienogest exerts anti-proliferative, and anti- angiogenic properties in experimental endometriosis Dienogest is the only low-dose progestin that has been shown to : Efficacy significantly superior to placebo Be equally effective to current standart therapy with gonadotropin – releasing hormone agonists, such as leuprolide acetate and buserelin acetate Have a favorable safety and tolerability profile Be suitable for long-term use in endometriosis Dienogest is a well-tolerated and effective therapy for reducing pain related to endometriosis

53. Dienogest 2mg significantly reduces lesion rAFS score by week 24 Visible reduction in lesions : In >80% of patients , no or only minimal endometriosis was detec-table at a 2nd LPS at 24 wks At Time of Menstruation Prior to DNG Therapy Following 24 Weeks of DNG Therapy 68 women 6 months

54. 1106 cases of conservative surgery for endometriosis Ovarian Pelvic Deep Ovarian & Deep 4 years Recurrence rate 24,6% 17,8% 30,6% 23,7% 8 years Recurrence rate 42% 24,1% 43,4% 30,9% American Journal of Obstetrics and Gynecology (2006) 195, 426–32

55. Dienogest 2 mg: Side effects profile Parameters Platelets Partial thromboplastin time Thrombin Time Protein C Protein S Antithrombin III Activated protein C resistance Homocysteine Mean (SD) Value 193.1 ± 49.1/nl 26.3 ± 6.5 sec 14 ± 5 sec 102.3 ± 12.5% 106.1 ± 8.7% 101.8 ± 16.1% 3.4 ± 0.8 9.9 ± 2.5 µ mol/l Reference Range 140-400/nl 22-32 sec 14-22 sec 70-140% 55-124% 79-110% >2.30 ratio <12.5 µ mol/l Parameters GPT (ALT) GOT (AST) Gamma-glutamyl Transpeptidase Alkaline phosphatase Result 22.3 ± 7.4 25.9± 6.5 26.7 ± 7.0 70.9 ± 16.1 Reference range < 35 U/I <35 U/I <40 U/I <105 U/I Parameters Lipoprotein Cholesterol LDL/HDL ratio Triglyceride Result 12.5 ± 5.3 mg/dl 173.6 ± 6 mg/dl 3.0 ± 0.8 133.1± 17.4 mg/dl Reference range < 30 mg/dl >200 mg/dl <4.0 <150 mg/dl Hemostasis parameters Lipid metabolism Liver enzymes Romer T. 2nd SEUD Congress, 12-14th May 2016 Barcelona, Spain

56. Clinical studies with long-term (>12 month) use of DNG Study countries n 1 2 3 4 5 6 7 8 9 10 11 Reference Yarmolinskaya M et al., poster at SEUD, 12-14 May 2016, Barcelona. 2. Park SY et al., Clin Exp Reprod Med. 2016; 43: 215–220. 3. Petraglia F et al. Arch Gynecol Obstet 2012;285:167–173. 4. Ota Y et al. J Endometr Pelvic Pain Disord 2015;7:63–67. 5. Momoeda M et al. J Obstet Gynaecol Res 2009;35:1069–1076. 6. Adachi K et al. Gynecol Endocrinol 2016;32:646-649 . 7. Sugimoto K et al. J Obstet Gynaecol Res 2015;41:1921–1926. 8. Roemer T. Poster 1575 at SEUD, 12–14 May 2016, Barcelona . 9. Kitawaki J et al. Eur J Obstet Gynecol Reprod Biol 2011;157:212–216. 10. Takagi H et al. Abstract 0671 at FIGO, 7–12 October 2012, Rome. 11. Angioni S et al. Gynecol Endocrinol 2015;31:406–408.

57. Dienogest efficacy in patients with endometrioma reccurence Dynamics of unilateral endometriomas size: In 12 months – from 30,9 to 20,8 mm In 18 months – from 20,5 to 14,7 mm Dynamics of bilateral endometriomas size: In 12 months – from 68,2 to 36,8 mm In 18 months – from 50,7 to 41,5 mm So Yun Park et al. Efficacy and safety of dienogest in patients with endometriosis: a single-center observational study over 12 months. Clin . Exp. Reprod . Med. 2016, 43 (4):215-220 Women with endometriosis who had been treated with 2 mg of dienogest once a day for 12 months or more. The size of the recurrent endometrioma was significantly decreased at the 12-month and 18-month follow-ups.

58. Effect of dienogest on pain and ovarian endometrioma occurrence after laparoscopic resection of uterosacral ligaments with DIE Prevalence of endometriomas Prevalence of endometriosis-related pain ( VAS score ≥ 4) Dienogest 5 % Dienogest 6,7% No medication 31,3% No medication 43.2% No medication group (%) DNG group (%) Number of patients 67 59 Treatment duration - 31±17.6 months Duration of observation (months, means SD) 28±17.6 35 ±17.6 . Yamanaka A. et al. Eur J Obstet Gynecol Reprod Biol. 2017 Sep;216:51-55.

59. Minimal change in bone mineral density and no increase in hot flushes with Dienogest 2 mg Data from comparison study vs. Leuprolide acetate: *mean ± SEM: Standard error of the mean; BMD: bone mineral density; LA: leuprolide acetate; Strowitzki T et al. Hum Reprod 2010; 25: 633–641 % change in BMD* P=0.0003 at 24 weeks Weeks of treatment 24 Weeks of treatment 60 Hot flushes (days per week)*

60. Dienogest Placebo Long-term DNG over 5 years for recurrence prevention after endometrioma surgery 568 women (32 . 8±5 .7 years ) 151 dienogest 417 placebo 5 year duration of observation 60 months dienogest usage Endometrioma recurrence : Placebo 69%, dienogest 4% Ota Y et al . J Endometr Pelvic Pain Disord 2015; 7(2): 63 – 67.

61. Estradiol levels during Dienogest 2 mg treatment remain within suggested therapeutic window Klipping C et al. J Clin Pharmacol 2012; 52: 1704–1713. Barbieri RL. J Reprod Med 1998; 43: 287–292. 25 50 75 100 125 150 10 20 30 10 20 30 40 50 60 70 80 91.8 183.5 275.3 367.1 458.9 550.6 Estradiol ( pg /ml) Pre-treatment (days) Treatment (days) Estradiol ( pmol /L) Pre-treatment Treatment with Dienogest 2 mg 62

62. Fertil Steril 2017;107:533–6 Endometriosis implants , demonstrate resistance to progesterone and have augmented estrogen activity The dose of EE in a low -dose OCP is equivalent to 4 to 6 times the physiologic dose of estrogen Supraphysiologic concentrations of estrogen with the OCP, may rescue endometrial cell clusters deposited in the pelvis during retrograde menses Oral progestins alone PROS Fertil Steril 2017 ;107:533–6 How About COC ?

63. COCs may be ineffective because they cause estrogen dominance in the presence of progesterone resistance In the normal endometrium, there is fine regulation of estrogen and progesterone activity 1,2 In endometriosis, there is complete loss of the progesterone receptor (PR-B) activity 1,2 This results in loss of progesterone signalling and augmented estrogen activity COCs deliver estrogen and progestin, which act counterproductively 3 Progestin antagonizes the estrogen effect on the endometrium A higher than physiologic dose of estrogen is also provided The estrogen -progesterone disequilibrium remains The estrogen component may result in stimulation of the disease 64 COC, oral contraceptive pill Bulun et al Semin Reprod Med. 2010, 28(1):36–43; Bulun et al Semin Reprod Med. 2010, 28(1):44–50; 3. Casper et al Fertil Steril . 2017, 107(3):533-536

64. Only one study has evaluated the effectiveness of COCs in treating dysmenorrhea associated with endometriosis 1 65 COC, oral contraceptive pill 1. Casper et al Fertil Steril . 2017, 107(3):533-536; 2. Harada et al Fertil Steril . 2008, 90(5):1583-1588 Change in mean dysmenorrhea score in a randomized, placebo-controlled trial in patients with endometriosis (n=100) 2 Total dysmenorrhea score ( mean±SD ) COC use for 4 months was associated with a 50% reduction in dysmenorrhea, but no beneficial effect on non-menstrual pelvic pain and dyspareunia was observed 2

65. Several non-controlled studies have investigated the treatment of endometriosis-associated pain with COCs 66 In a retrospective, chart review of women diagnosed with chronic pelvic pain from January 2003 to December 2005 (n=104): COC, oral contraceptive pill Jenkins et al J Minim Invasive Gynecol. 2008, 15(1):82–86. 47 (45%) of women had partial to complete relief of symptoms Patients who achieved pain relief (86%) were as likely as those who failed to respond to COCs (85%) to have endometriosis All hormonal treatment COC GnRHa

66. Past COC use may be associated with an increased risk of endometriosis 67 *OC use was adjusted for age, gravidity, infertility, dysmenorrhea and OC use for primary dysmenorrhea. COC, oral contraceptive pill Chapron et al Hum Reprod 2011, 26(1):2028–2035. Cross-sectional study investigating patients without visible endometriosis and those with histologically proven endometriosis (n=976) Superficial Deep infiltrating Ovarian endometrioma Past OC users had a significantly increased risk of superficial and deep infiltrating endometriosis

67. In clinical practice, COCs cannot be prescribed to all women May cause problems for women with endometriosis looking to conceive in the future 68 COC, oral contraceptive pill 1. Black et al J Obstet Gynaecol Can 2015, 37(1):1033–1039; 2. Talukdar et al Obstet Gynecol 2012, 120(1):348–354 Contraindications for prescription of COCs 1 : Female smokers > 35 years Women at increased risk of myocardial infarction, stroke, or venous thromboembolism Prolonged COC use may result in endometrial thinning that is non-responsive to estrogen 2

68. Dienogest 2 mg is an easy-to-use oral agent with favorable safety profile, effective for long-term treatment of endometriosis 1–7 Dienogest 2 mg can be prescribed to patients awaiting surgery for symptom relief 1–5 Use of Dienogest 2 mg after surgery may reduce the risk of recurrence 6,7 In summary … 1. Yarmolinskaya M et al., poster at SEUD, 12-14 May 2016, Barcelona. 2. Park SY et al., Clin Exp Reprod Med. 2016; 43: 215–220. 3. Petraglia F et al. Arch Gynecol Obstet 2012;285:167–173. 4. Momoeda M et al. J Obstet Gynaecol Res 2009;35:1069–1076. 5. Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol. 2010; 151:193–198 6. Adachi K et al. Gynecol Endocrinol 2016;32:646-649. 7. Ota Y et al. J Endometr Pelvic Pain Disord 2015;7:63–67. Educating Patient before start the treatment would be a very important part for ensuring patient compliance to treatment

69. Endometriosis Consensus HIFERI 2017 70

70. SIDE EFFECT MEDICAL THERAPY PROGESTIN BONE LOSS ANDROGENIC EFFECT MENOPAUSE SIGN THROMBO EMBOLIC RISK ANTI PROLIFERATIVE ANTI ANGIOGENIC ANTI INFLAMMATORY DMPA ↓↓↓ - - - + - - DANAZOL - +++ - - + - - DIENOGEST ± - - - + + + GnRHa ↓↓↓ - + - + + - OCP - - - + + - -

71. Terima kasih

72. KEKAMBUHAN ENDOMETRIOSIS PASCA OPERASI Abstract: Objective: To assess the remission rate and outcome of pregnancy of patients who had moderate and severe ovarian endometriosis after conservative surgery. We also wished to analyze the associated factors of recurrence. Methods : Weconducted retrospective analyses of 199 cases with stage II-IV ovarian endometriosis who had preserved fertility under laparoscopic surgical treatment. Postoperatively, the 199 patients were divided into three groups: 43 cases underwent surgical treatment alone (group A); 47 were given a gonadotropin -releasing hormone agonist ( GnRH -α) (group B), and 109 were given mifepristone (group C). Ten cases in group A were infertile, 26 cases in group B, and 38 cases in group C. All patients were followed up for 3 years.

73. Results: In groups A, B and C, the remission rate was 58.13%, 70.21% and 60.55% and the difference not significant (P=0.384); Recurrence rates were 27.90 %, 12.76% and 24.77%, and the difference between them significant (P<0.05). The recurrence rate in group B was the lowest. The natural pregnancy rate after surgery in the three study groups (untreated, GnRH -α and mifepristone ) was 30%, 34.61% and 28.94% but this difference was not significant. Conclusion: Surgery can improve the symptom remission rate and fertility of patients. Postoperative drug therapy does not improve the chance of pregnancy. KEKAMBUHAN ENDOMETRIOSIS PASCA OPERASI

74. Tabel. Recurrence rate and the relationship between post operative adjuvants KEKAMBUHAN ENDOMETRIOSIS PASCA OPERASI Ke Xiaoping et al.,2015

75. KEKAMBUHAN ENDOMETRIOSIS PASCA OPERASI RESULT : The cumulative rates of pain recurrence, clinical or sonographic recurrence, and new treatment were 28%, 34%, and 27%, respectively. The younger patients had the higher risk of recurrence. Pregnancy had protective effects against the recurrence of symptoms and a need for a new treatment. Patients who underwent bowel resection had fewer recurrences. CONCLUSION : Segmental resection and anastomosis of the bowel, when necessary, improves the outcome without affecting chances of conception. Higher recurrence rates in younger patients seems to justify a more radical treatment in this group of women

76. RESULTS: Age at surgery was the only significant risk factor for recurrence, at a cut-off of 32 years, obtained through receiver-operator curve analysis. In patients not receiving medication, the recurrence rate gradually increased up to 50% over 5 years; there was no recurrence 5 years after surgery. Although no recurrence was seen in patients during continuous treatment with OCP or dienogest , the disease recurred in 55.5% of patients after discontinuing OCP. CONCLUSIONS: Although adjuvant therapy for all patients may represent overtreatment, the findings of the present study suggest that, in the interest of fertility preservation, continuous postoperative hormonal treatment should be administered, at least to patients younger than 32 years. In patients who decline hormonal treatment, we recommend that they undergo follow-up for recurrence until 5 years after surgery. KEKAMBUHAN ENDOMETRIOSIS PASCA OPERASI

77. Gejala Klinis Gejala khas : Nyeri ketika haid Nyeri Premenstrual Nyeri ketika berhubungan seksual Nyeri pelvis difus / kronik Gejala lain: Gejala Perimenstrual symptoms (e.g. terkait dengan usus atau kandung kemih ) Nyeri punggung Kelelahan kronis Sejumlah kasus ditemukan asimptomatik Sulit mendiagnosa bila hanya dengan gejala klinis saja Gejala yang timbul bervariasi tiap individu Mirip dg kondisi penyakit lain: irritable bowel syndrome; pelvic inflammatory disease 79 Sinaii N, Plumb K, Cotton L et al. Fertil Steril 2008.

78. Relationship between endometriosis and adenomyosis N Adenomyosis No endometriosis 55 22 (40.0 %) Endometriosis 237 153 (64.6%) Total 292 175 (59.9%) Chapron et al., Hum Reprod (2017)

79. Relationship between endometriosis and adenomyosis Osis Patients phenotype N DIFFUSE Adenomyosis FOCAL Adenomyosis Control 55 20 (36.4%) 3(5.4 %) Endometriosis 237 81 (34.2%) 119 (50.2%) SUP 40 8 (20.0%) 3 (7.5%) 31 14 (45.2%) 6 (19.3%) DIE 166 59 (35.5%) 110 (66.3%) Chapron et al., Hum Reprod (2017)

80. Inflammatory response pathway leads to tissue injury and chronic pain Inflammation Regurgitation ↑ Iron Decreased anti-inflammatory factors Increased pro-inflammatory factors Oxidative Stress ↑ NF-K β ↑ TNF- α ↑ IL-1β ↑ IL-6,8,33 ↑ Rantes ↑ PGs Tissue injury Excessive sensory innervation Neuroangiogenesis ↓ CXCL 10 ↓ IL-19,22 Pelvic Pain ↑ NGF ↑ PGs

81. Definition Presence of endometrial tissue outside the lining of the uterine cavity or Proliferation of endometrium in any side other than the uterine mucosa

82. Personal approach Global approach Patients and Endometriosis Pelvic pain Infertility Uterine bleding SUP OMA DIE Adenomyosis Imaging Endocrinology Surgery ART Multidisciplinary management

83. Manajemen Jangka Panjang yang ideal 85

84. Endometriosis-related pelvic pain : Medical treatment options Painkillers, including anti-inflammatory drugs Combined Oral Contraceptives (COCs) ± Continuosly Progestins alone (oral, IUD) GnRH-analogues ± add-back therapy

85. VAS (mm) mean ± SEM 10 20 30 40 50 60 12 65 Placebo DNG 2 mg/day DNG 2 mg (prior placebo) DNG 2 mg (prior DNG) TREATMENT-FREE EXTENSION STUDY PLACEBO STUDY Efficacy shown over 15 months Weeks of treatment 152 patients 53 weeks with + 24 weeks without

86. VAS (mm) mean ± SEM 10 20 30 40 50 12 65 Placebo DNG 2 mg/day DNG 2 mg (prior placebo) DNG 2 mg (prior DNG) TREATMENT-FREE EXTENSION STUDY PLACEBO STUDY Weeks of treatment Sustained efficacy … . administered for prolonged period of time.. 152 patients 53 weeks with + 24 weeks without

87. Irregular bleeding patterns during DNG In contrast to previous reports, the rate of amenorrhea was much higher, reaching ~60% at 3 months and ~90% at 18 months 1 1. Lee SR et al. Efficacy and Safety of Long-Term Use of Dienogest in Women With Ovarian EndometriomaReproductive Sciences 2018, Vol. 25(3) 341-346; 2. Petraglia F, et al. Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment. Arch Gynecol Obstet. 2012;285(1):167-173; 3. Momoeda M, et al. Long-term use of dienogest for the treatment of endometriosis. J Obstet Gynaecol Res. 2009;35(6):1069-1076. Retrospective cohort study investigating the effectiveness of dienogest 2 mg on post-operative recurrence of ovarian endometrioma (N=514) A(amenorrhea) P(prolonged bleeding) S(spotting) F(frequent bleeding) R(regular) mens Time Number of patients Menstrual patterns during dienogest (DNG) use Baseline 12 weeks 24 weeks 48 weeks 72 weeks 50 100 150 200 250 300 350 400 Menstrual Pattern during Dienogest treatment

88. 16.5% 24% Recurrent endometriomas were diagnosed in 3 patients (1.5%). Mean follow-Up 30.2±20.9 months Adachi K et al. Gynecol Endocrinol . 2016 Aug;32(8):646-649. Epub 2016 Feb 18. PubMed PMID: 26890948 Chandra A et al. Obstet Gynecol Sci. 2018 Jan;61(1):111-117. Epub 2017 Dec 18. PubMed PMID: 29372157 Lee SR et al. Reprod Sci. 2018 Mar;25(3):341-346. Epub 2017 Nov 21. PubMed PMID: 29161960 The recurrence rate of endometrioma was 1.8% (9 of 514). Average DNG administration was 72.2 + 5.2 weeks (range: 48-164). Follow-up 41 months Dienogest post-surgery is associated with reduced rates of recurrence

89. 1 0.8 0.6 0.4 0.2 Recurrence-free subjects 6 12 18 24 30 36 Months Oral dienogest 1mg bid (n=40) Expectant management (n=41) Adachi K et al. Gynecol Endocrinol 2016; 32:646–649 Dienogest is associated with significantly greater reduction in pain post-surgery 1 24 months post-surgery 1 : 24.0% recurrence for expectant management vs 0% for DNG Dienogest post-surgery is associated with reductions in recurrence and pain

90. Relevance of estradiol levels in endometriosis Figure adapted from Barbieri RL. J Reprod Med 1998; 43: 287–292.Klipping C et al. J Clin Pharmacol 2012; 52: 1704–1713 pg /mL 100 10 Maximal response (%) 80 60 40 20 20 30 40 50 60 70 80 90 100 Atrophy of endometrial lesions Stimulation of endometrial lesions Substantial bone loss Minimal bone loss Estradiol concentration ( pg /mL) Endometrial lesion growth Bone turnover Mean estradiol levels with DNG 2 mg were 39 pg /mL 1 Endometriotic lesion growth and bone loss are minimized 92

91. KEKAMBUHAN ENDOMETRIOSIS PASCA OPERASI