Emerging treatment of endometriosis


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Emerging treatment of endometriosis

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Emerging treatment of endometriosis

  1. 1. Aboubakr Elnashar Benha university hospital Emerging treatment of endometriosis Aboubakr Elnashar
  2. 2. Introduction Endometriosis: estrogen-dependent disorder substantial morbidity: pelvic pain infertility. Multiple operations Aboubakr Elnashar
  3. 3. Current treatment: Ovarian suppressive agents. Oral contraceptive Progestins GnRha Androgenic agents Surgery Aboubakr Elnashar
  4. 4. Outcome of current TT: 1. Pain relief: Only half of patients 2. Fertility: No benefit Delayed conception 3. Disease: No eradication Recurrence (disease, symptoms): quite common. 4. SE: Unwanted {hypoestrogenic state}: limit the long-term use. Aboubakr Elnashar
  5. 5. For these reasons, new drugs that aim new targets are required An ideal treatment for endometriosis: Regression of the disease & symptoms No adverse hypoestrogenic effects Literature review in last 5 y Aboubakr Elnashar
  6. 6. LNG-IUD GnRHan Aromatase inhibitors SERM Progesterone antagonist SPRM Angiogenesis inhibitors Immunomodulatory drugs. Others Aboubakr Elnashar
  7. 7. DrugsGroup Mirena1. LNG-IUD Cetrorelix2. GnRHan Anastrazole (Arimidex), Letrozole (Femara) 3. Aromatase inhibitors Tamoxifen, Raloxifene4. SERM Mifepristone, Onopristone5. Progesterone antagonist Asoprisnil6. SPRM TNP470, Endostatin, Anginex, Rapamycin 7. Angiogenesis inhibitors Loxoribine, IFN- α 2 β, TNF- α inhibitors. 8. Immunomodulatory drugs. Matrix metalprotease, Doxycycline, 5-fluorouracil, Thiazolidinediones 9. Others Aboubakr Elnashar
  8. 8. I. Levonorgestrel-releasing intrauterine device (LNG-IUD) Oral progestogens: poor compliance systemic SE. Aboubakr Elnashar
  9. 9. LNG-IUD T-shaped Release rate of LNG: 20 μg/24 h during 1st y slowly ↓ throughout the 5 y of use. : Endometrial atrophy Ovulation: usually not suppressed. Contraception Hypomenorrhea or amenorrhea Reduced dysmenorrhea Aboubakr Elnashar
  10. 10. Mechanism of action: Unclear LNGIUD delivers significant amounts of LNG into the peritoneal fluid: clearing up the local effect on the endometriotic implants mediated through estrogen& progesterone receptors: decidualization. {peritoneal fluid levels of LNG were closely related to the levels in serum}: hematogenous mechanism by which LNG reaches the peritoneal cavity. Aboubakr Elnashar
  11. 11. Studies: 1. Peritoneal as well as rectovaginal endometriosis: Great improvement in pain control Reduction in size (Vercellini et al, 1999; Fedele et al,2001). 2. Minimal to moderate endometriosis: Significant reduction of pain as well as stage Continuation rate: 68% after 6 ms Adhesions: as expected, not altered (Lockhat et al, 2004) Aboubakr Elnashar
  12. 12. 3. Symptomatic endometriosis 12 ms after surgery dysmenorrhea scores were significantly lower [Crosignani, 2003]. 4. Stage I–IV endometriosis LNG-IUS & GnRHa were effective in TT of chronic pelvic pain -associated endometriosis No differences between the two treatments [Petta et al, 2007] Aboubakr Elnashar
  13. 13. 5. Postoperative use of the LNG-IUD reduces the recurrence of painful periods (Cochrane systematic review, 2006) . Aboubakr Elnashar
  14. 14. Conclusion LNG-IUD Treatment of choice for CPP-associated endometriosis in women who do not wish to conceive. {1. Effective for at least 5 ys 2. Can be reapplied every 5 ys. 3. No modifications in estrogen levels 4. In the long term it is a low-cost therapy 5. Fewer SE than other progestogenic agents. Aboubakr Elnashar
  15. 15. II. GnRH antagonists GnRHa: ↑LH & FSH: ↑E2: ↑pelvic pain: ↓quality of life (Miller , etal, 2000) limited to the first 5 to 10 d. Aboubakr Elnashar
  16. 16. Mechanism of action: GnRHan immediately block GnRH effects competing with endogenous GnRH for pituitary binding sites suppress LH secretion in a dose-dependent manner. Aboubakr Elnashar
  17. 17. Uses Endometriosis Leiomyoma Breast cancer Premenstrual syndrome PCOS Superovulation in IVF Aboubakr Elnashar
  18. 18. Studies: 3 mg of cetrorelix/w for 8 w E2: suppressed to 50 pg/ml. 100%: symptom-free period during GnRH TT 50%: Regression 2nd look laparoscopy: Degree of endometriosis declined to a mild stage (Kupker et al, 2002). Aboubakr Elnashar
  19. 19. Conclusion: GnRHan 1. useful in TT of endometriosis in most cases. 2. Fewer SE e.g. postmenopausal symptoms 3. No estradiol add-back is needed. 4. Superior to GnRHa {immediate suppression of LH and FSH secretion: avoid the agonist phase of GnRHa}.  In the future: oral GnRHan: improve patients’ comfort &compliance. Aboubakr Elnashar
  20. 20. III. Aromatase inhibitors (AIs) Aromatase enzyme •Responsible for: Conversion of androgens to estrogens (E1& E2). •Localized primarily in: 1.Ovarian granulosa cells in premenopausal women 2. Other tissues: liver, brain. 3. After menopause: adipose tissue is the principle source of estrogens. Aboubakr Elnashar
  21. 21. 4. In Normal endometrium: No detectable levels of aromatase activity In endometriosis: An increased expression of cytochrome P450 aromatase in endometrial tissue {inflammatory mediator prostaglandin E2: increase local estrogen production} Aboubakr Elnashar
  22. 22. 3rd generation AIs Potent, specific & better tolerability than the former compounds. Types: i-Steroidal derivatives: Exemestane (Aromasin) approved in USA. ii-Non-Steroidal imidazole derivatives: Fadrozole. iii-Non-Steroidal triazole derivatives: Anastrazole (Arimidex) Letrozole (Femara) Both are approved in USA for the treatment of breast cancer. Aboubakr Elnashar
  23. 23. Absorption & metabolism • Letrozole: Rapidly& completely absorbed from GIT. Elimination half-life: 2 d Aboubakr Elnashar
  24. 24. Uses of AIs 1. Breast cancer (FDA approved) 2. Endometrial carcinoma & endometrial stromal sarcoma 3. Endometriosis 4. Induction of ovulation 5. Unexplained infertility 6. Poor responders Aboubakr Elnashar
  25. 25. Mechanism of action in endometriosis Estrogen is produced by 3 pathways 1. Hypothalamic-pituitary-ovarian pathway 2. Peripheral conversion 3. Locally within endometriosis.  GnRHa stops only 1st pathway  AI stop all 3 pathways •Decreasing aromatase in the brain: decrease LH& FSH: decrease estrogen •Suppress ovarian & peripheral (e.g. adipose tissue) estrogen production. Aboubakr Elnashar
  26. 26. Mechanism in induction of ovulation 1. Initial response to AI: ↓estrogen levels: ↑FSH and LH: directly stimulates the ovary: ↑number of mature follicles (Mitwally & Casper, 2001). 2. locally in the ovary: ↑ follicular sensitivity to FSH (Vendola et al,1998). Aboubakr Elnashar
  27. 27. Studies I. Postmenopause: 1. Severe recurrent endometriosis Anastrozole: complete relief of pain after 2 ms (Bulun et al,1999). 2. Endometriosis-associated pain Letrozole was effective (Mousa et al,2007) 3. Large recurrent abdominal wall endometrioma: AI plus progestin & serial cyst aspiration: successful TT (Sasson et al, 2009) Aboubakr Elnashar
  28. 28. II. Premenopause: AI alone may induce ovarian folliculogenesis: AIs are combined with progestin, COC, or GnRHa {prevent reflex increments in LH and FSH} Aboubakr Elnashar
  29. 29. 1. laparoscopically visible endometriotic lesions: letrozole (2.5 mg/day), norethindrone acetate (2.5 mg/day), calcium & vit D for 6 ms: Effective in reducing pelvic pain scores (Ailawadi et al,2004). Aboubakr Elnashar
  30. 30. 2. Endometriosis failed to respond to COC& GnRHa: Anastrozole (1mg/d) with progestin (200 mg/d) for 6 ms: Rapid reduction in symptoms Remission of symptoms & absence of endometriotic lesions for >2 ys Pregnancy in both cases after 2 ys. SE: minimal (Shippen& West 2004). Aboubakr Elnashar
  31. 31. 3. Endometriosis with severe pelvic pain Anstrazole (1mg daily) Vs Goserelin (3.6 mg, SC) for 6 mo: SE & relapse after 1y: similar (Muderris, 2002) Aboubakr Elnashar
  32. 32. 4. Bladder endometriosis letrozole (2.5 mg/day), norethisterone acetate (2.5 mg/day), calcium &vit D3 for 6 ms: Both patients: improved pain & urinary symptoms One patient: myalgia & severe arthralgia; pain & urinary symptoms recurred few months after the interruption of the 6-m: laparoscopic partial cystectomy. These agents should be administered only to patients who refuse surgery & fail to respond to other therapies. (Ferrero, 2010). Aboubakr Elnashar
  33. 33. 5. Refractory pain from endometriosis who failed to other therapies Anastrozole 1 mg for 6 ms & COC continuous: Decrease in pain scores (Amsterdam et al, 2005) Aboubakr Elnashar
  34. 34. 6. Recurrent endometriotic cysts Letrozole (2.5 mg), COC, calcium (1,200 mg), & vit D3 (800 IU) daily for 6 ms: Complete regression of the cyst Pain relief in all cases No significant change in bone density (Seal et al, 2011) Aboubakr Elnashar
  35. 35. 7. Post operative surgery for severe endometriosis Anastrozole (1 mg/day) & goserelin Vs goserelin alone for 6 mo: ↑ pain-free interval ↓symptom recurrence rates (Soysal et al, 2004). Aboubakr Elnashar
  36. 36. 8. Class IV endometriosis GnRHa ( Goserelin, 3.6 mg SC/4w) plus Anastazole (1 mg daily) for 6 ms Vs GnRHa alone SE: similar In anstrazole-agonist group: Relapse is less (10% Vs 38%) Pregnancy rate is higher (47% Vs 17%) (Scarpellini & Sbracia, 2000) Aboubakr Elnashar
  37. 37. 9. Severe endometriosis Anstrazole (1 mg/d from the start of the agonist to the beginning of HMG) in the long protocol of COH, for IVF,. •In letrozole-agonist group: PR: higher (21.7 & 23.8 % Vs 3.6% & 4.3%). {The lowest E2 just before HMG administration}. (Krasnopol & Kaluina, 2002) Aboubakr Elnashar
  38. 38. AI for ovulation induction. Pain: continuously Ov induction: cyclically Not FDA approved Black box warning regarding using in pregnancy Chromosomal anomalies as well as major congenital malformations: the same in the CC and letrozole group (Tulandi et al,2006). Aboubakr Elnashar
  39. 39. Side effects: Rare Headache (6.9%) Nausea (6.3%), Peripheral edema (6.2%) Fatigue (5.2%), Hot flushes (5.2%) Bone&back pain(4.8%) Hair thinning and rash (3.4%) Osteoporosis {decrease E in local tissues}: Controversial No change in BMD at 6 ms after use of an AI with COC Decrease in BMD with the use of AI with a GnRH agonist after 6 ms (Soysal et al, 2004). Aboubakr Elnashar
  40. 40. Conclusion 1. All 3 combinations decrease pain in patients with refractory endometriosis. 2. Combinations of an AI with a progestin or COCs will become more popular than combinations of an AI with a GnRHa {cheaper, fewer side effects} 3. No severe SE 4. AIs should be offered to women who have severe pain despite previous surgical& hormonal therapies. 4. Further research is required before recommending the routine use of these agents. Aboubakr Elnashar
  41. 41. Conclusion 1. LNG-IUD Treatment of choice for CPP-associated endometriosis in women who do not wish to conceive. 2. GnRHan useful in TT of endometriosis in most cases and superior to GnRHa 3. AIs should be offered to women who have severe pain despite previous surgical& hormonal therapies. should be combined with a progestin or COCs Aboubakr Elnashar
  42. 42. IV. Selective estrogen receptor modulators (SERMs) SERM: Can act as either estrogen agonists or antagonists depending on the target tissue Can be directed towards the αor βsubunits of Ers 1st generation: Tamoxifen 2nd generation: Raloxifene Aboubakr Elnashar
  43. 43. Uses: 1. Prevention osteoporotic fractures in postmenopause 2. Prevention of breast cancer. 3. Endometriosis (SERM directed towards β subunits) {antiestrogenic effect on endometrial tissue}. Aboubakr Elnashar
  44. 44. Studies: In mice: SERM directed towards the β –subunit: resolved endometriosis in 40 – 75% (Harris et al, 2005). In human: No studies Aboubakr Elnashar
  45. 45. V. Progesterone antagonist An oral active progesterone antagonist at the receptor level. High affinity for progesterone and glucocorticoid II receptors. Mifepristone (RU-486) Onopristone use in medical abortions Aboubakr Elnashar
  46. 46. Mechanism of action: 1. Antiprogesterone effect: prevents progesterone from exerting its action. 2. Direct inhibitory effect on human endometrial cells 3. Modulate the estrogen and progesterone receptor expression in both eutopic and ectopic endometrium. Aboubakr Elnashar
  47. 47. Studies: 1. In Rodent: promising effects (Tjaden et al, 1993; Stoeckermann, 1995). 2. In human: 50 mg mifepristone for 6 ms: Significant regression in visible endometriotic Decrease in clinical symptoms. SE with doses of ≥ 200 mg {antangonistic affinity of the drug to glucocorticoid receptors causing a hypoadrenal state}. (Kettel et al, 1998) Aboubakr Elnashar
  48. 48. Conclusion: Further large RCT should be performed Aboubakr Elnashar
  49. 49. VI. Selective Progesterone receptor modulators (SPRM) SPRM: agonist/antagonist effects based on the target tissue, dose and presence or absence of progesterone. progesterone receptor ligands with a high degree of endometrial selectivity Asoprisnil Aboubakr Elnashar
  50. 50. Rationale for the treatment of endometriosis. 1. Induce reversible amenorrhea {selective inhibition of endometrial proliferation, a direct effect on endometrial blood vessels} 2. Suppress endometrial prostaglandin production in a tissue-specific manner without the systemic effects of estrogen deprivation Asoprisnil: suppress both the menstrual cycle and endometrial growth (DeManno et al, 2003). Aboubakr Elnashar
  51. 51. Studies: 1. Endometriosis with moderate or severe pelvic pain asoprisnil (5, 10 and 25 mg/day) for 12 w: Reduced pelvic pain as well as dysmenorrhea; Effect on bleeding pattern was dose-dependent (Chwalisz et al, 2004). 2. 5 mg is the minimum effective dose for pain relief (Chwalisz et al, 2005). Aboubakr Elnashar
  52. 52. Benefits. 1. In relationship to antiprogesterones, they are more specific for the progesterone receptors: not inhibiting the glucocorticoid receptors 2. No serious SE 3. No signs of estrogen deprivation Aboubakr Elnashar
  53. 53. VII. Angiogenesis inhibitors Angiogenesis is a prerequisite for endometriosis development. {Retrograde menstruation: peritoneal endometriotic lesions. Endometrial tissue requires the establishment of a new blood supply in order to survive in the peritoneal cavity. The endometrium has angiogenic potential, and endometriotic lesions grow in areas with a rich vascularization} Aboubakr Elnashar
  54. 54. Rationale: Inhibition of proangiogenic factors e.g. VEGF and MMPs Angiostatic drugs TNP470 Endostatin Anginex Rapamycin Aboubakr Elnashar
  55. 55. Studies 1. In mouse: Angiostatic compounds: effective in reducing the growth of endometriotic (Nap et al, 2004). 2. In human: Thalidomide {angiostatic & immunomodulatory} effective in women with relapsing endometriosis (Scarpellini et al, 2002). Aboubakr Elnashar
  56. 56. 3. Statin: a. TT of heart disease and prolong life expectancy {lower blood cholesterol} b. reducing the risks of diabetes, dementia and osteoporosis. c. inhibit the growth of human endometrial stromal cells in vitro (Piotrowski et al, 2006). Aboubakr Elnashar
  57. 57. 4. Rapamycin a. antifungal, immunosuppressant and antiangiogenic effects. b. Regression of endometriotic lesions {inhibiting neovascularization and cell proliferation}. Inhibition of VEGF-mediated angiogenesis (Laschke et al, 2006) Aboubakr Elnashar
  58. 58. 5. Dopamine agonists a. Cabergoline (Cb2) In experimental endometriosis Cb2 treatment in has an anti-angiogenic effect acting through VEGFR-2 activation. A significant decrease in endometriotic lesions and cellular proliferation index (Novella-Maestre et al, 2009). Aboubakr Elnashar
  59. 59. b. Quinagolide Endometriosis-associated hyperprolactinemia 70% reduction in the size of the lesions 35% vanishing completely. {interfering with angiogenesis, enhancing fibrinolysis, and reducing inflammation} quinagolide reduces or eliminates peritoneal endometriotic lesions (Gomez et al, 2011). Aboubakr Elnashar
  60. 60. Limitations and challenges (Langendonckt et al, 2008). 1. Antiangiogenic treatments may alter reproductive function by impairing physiological angiogenesis, the greatest concern being the potential risk of teratogenicity. 2. The initial promise of vascular therapy has not yet been fulfilled {limited selectivity}. 3. Combining angiostatic agents and VDAs with medical and surgical therapies in an adjuvant setting may be the quickest and most efficient way of enhancing current treatment modalities. Aboubakr Elnashar
  61. 61. Conclusion 1. Vasculature is a promising target because of its genetic stability, easy access via the circulation and amplifying action during treatment. 2. Antiangiogenic drugs reduce the establishment, maintenance and progression of endometriotic lesions in different laboratory and animal models 3. The role of antiangiogenic compounds in the treatment of endometriosis remains to be defined 4. Further investigations are required before clinical trials can be planned in humans. Aboubakr Elnashar
  62. 62. 5. It is unlikely that antiangiogenic drugs may cure the symptoms caused by large endometriotic nodules that are mainly composed by fibromuscular tissue; on the contrary, these agents may have a role in the postoperative treatment of endometriosis to increase the pain free interval and decrease the recurrence of the disease. Aboubakr Elnashar
  63. 63. VIII. Immunomodulators Rationale: Altered immune function plays a crucial role in the genesis and development of endometriosis. Aboubakr Elnashar
  64. 64. Mechanism of action: Decreasing the inflammatory response to disease. Includes Loxoribine IFN- α 2 β TNF- α inhibitors. Aboubakr Elnashar
  65. 65. Studies: 1. Loxoribine: Stimulate natural killer cells, which then do not allow endometrial cells to implant in ectopic tissues. In rat: significant reduction in amount of disease (Keenan , 1999). Aboubakr Elnashar
  66. 66. 2. IFN- α 2 β intraperitoneal or by SC In animal models and in tissue cultures: decrease endometriosis (Ferrero, 2005). In human: intraperitoneal during surgery with a GnRHa postoperatively: increased recurrence risk after surgery (Acien & Quereda, 2002). Aboubakr Elnashar
  67. 67. 3. TNF-α inhibitors Mechanism of action: decreasing production or release of TNF- α from macrophages: preventing disease progression regression of early stage disease. Aboubakr Elnashar
  68. 68. a. Etanercept  Used: rheumatoid and autoimmune diseases. In the rodent and baboon model inhibit the development of endometriosis and endometriosis-related adhesions. (D’Antonio et al, 2000; D’Hooghe et al, 2001) In humans: Evidence is not so promising. No improvement of infertility or endometriosis (Shakiba et al, 2006). Aboubakr Elnashar
  69. 69. b. Infliximab Severe pain and a rectovaginal nodule 5 mg/kg No effect for any of the outcome measures. (Koninckx et al, 2008) Conclusion No enough evidence to support the use of anti-TNF- alpha drugs in the management of endometriosis for the relief of pelvic pain Aboubakr Elnashar
  70. 70. 4. Cytokines Interleukin-12 (IL-12) and IL-18: regulation of the adaptive immune response IL-12 induces other cytokines, particularly interferon- γ (IFN-γ) In a murine model: Intraperitoneal injection of IL-12 of endometriosis: significant reduction (Somigliana et al, 1999). Aboubakr Elnashar
  71. 71. 5. Pentoxifylline Mechanism of action: 1. inhibits phagocytosis and generation of toxic oxygen species and proteolytic enzymes by macrophages and granulocytes 2. inhibits both TNF-a production by macrophages, and the proinflammatory action of TNF-a and IL-1 on granulocytes Aboubakr Elnashar
  72. 72. 1. Minimal or mild endometriosis 800 mg/day oral for 12 ms No benefit for fertility (Balasch et al, 1997). 2. No significant effect on reduction of pain No evidence of an increase in clinical pregnancy events (Cochrane systematic review, 2009). Aboubakr Elnashar
  73. 73. IX. Others 1. Matrix metalprotease (MMP) Capable of degrading components of the extracellular matrix. Regulated by: tissue inhibitors of matrix metalloproteinase (TIMPs) Important in: 1. embryo implantation 2. cyclic endometrial breakdown 3. endometriosis Suppressing the action of secreted MMPs from human ectopic endometrium with TIMP-1significantly inhibited the establishment of endometriosis lesions in a nude mice model (Bruner et al, 1997). Aboubakr Elnashar
  74. 74. 2. Doxycycline (Dox) Inhibition of matrix metalloproteinase (MMP) activity. In a rat: Regression of endometriosis (Akkaya et al, 2009). Aboubakr Elnashar
  75. 75. 3. 5-fluorouracil [5-FU]). Rational: Common features between endometriotic cells and tumor cells Significantly decreased the proliferation of endometriotic cells in vitro controlled the growth of both cells from ovarian endometrioma and deep infiltrating endometriosis. (Ngô et al, 2010). Aboubakr Elnashar
  76. 76. 4. Thiazolidinediones: (TZDs) In animal models reduce endometriotic lesions. In human: Endometriosis-related pain. Rosiglitazone, 4 mg daily, for 6 ms: improvement in severity of symptoms and pain Rosiglitazone was well tolerated without impeding ovulation and without the need for add-back therapy. (Moravek et al, 2009) Aboubakr Elnashar
  77. 77. Thank you elnashar53@hotmail.comAboubakr Elnashar