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ENDOMETRIOSIS UPDATE Focus on Dienogest Dr Sharda jain dr Jyoti Agarwal

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ENDOMETRIOSIS UPDATE Focus on Dienogest Dr Sharda jain dr Jyoti Agarwal

  1. 1. Dr. Sharda Jain ENDOMETRIOSIS UPDATE Focus on Dienogest ISO 14001:2004 (EMS) …Caring hearts, healing hands
  2. 2. Over 350 ppts are available on slideshare.net ***for use of public/Doctors www.slideshare.net / Lifecarecentre
  3. 3. AGENDA • Background • What’s New in Endometriosis • Clinical Discussions in Managing Endometriosis • Newer Evidences on Dienogest • Bayer Holding 4:3 Template 2010 • July 2015
  4. 4. 1. Background Endometriosis
  5. 5. WHAT IS ENDOMETRIOSIS?  Endometriosis is defined as: – Chronic estrogen-dependent disease – Characterized by the presence of endometrial-like tissue outside the uterus, which – Induces a chronic, inflammatory reaction  While some women with endometriosis experience painful symptoms and/or infertility, others have no symptoms at all  Exact prevalence unknown: estimates range from 2 to 10% within the general female population and up to 50% in infertile women. Derived from ancient Greek: endo:‘inside’ and metra:‘womb’ * ESHRE guideline update 2013
  6. 6. 6 1 in 10 women have endometriosis during their reproductive years Crosignani P et al. Hum Reprod Update 2006; 12(2): 179–189.
  7. 7. Endometriosis – Prevalence Page 7 Endometriosis is a prevalent condition! Younger age at onset predicts more severe disease! 1. Ballweg ML et al. J Pediatr Adolesc Gynecol 2003; 2. Child TJ et al. Drugs 2001; 3. Cramer DW et al. Ann N Y Acad Sci 2002; 4. Bendigeri T et al. Indian Pract. 2015. As per recent estimates, about 176 million women suffer from Endometriosis globally; Of these, ~26 million women belong to India alone!! 4
  8. 8. Page 8
  9. 9. Endometriosis affects women during the prime years of their lives Nnoaham KE et al. Fertil Steril 2011; 96: 366–373. World Endometriosis Research Foundation prospective Global Study of Women’s Health
  10. 10. Sites commonly affected in Endometriosis ESHRE Guideline update 2013; Accessed at: http://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline.aspx
  11. 11. Endometriosis: The Lifelong Patient “Journey! The lifelong patient journey: Juggling pain management & fertility desires!
  12. 12. Diagnostic Delay in Endometriosis! Average of 7 primary care visits before specialist referral!!! 1. Nnoaham KE et al. Fertil Steril 2011; 96(2): 366–373. 2. Arruda MS et al. Hum Reprod 2003; 18: 756–759.
  13. 13. An Introduction to Dienogest 1. Background
  14. 14. Rationale for using Progestins in treatment of Endometriosis * Image courtesy of Prof. Michael Mueller, Inselspital, Bern, Switzerland Lazzeri L et al. J Endometriosis 2010; 2: 169–181. Kappou D et al. Minerva Ginecol 2010; 62: 415–432. CrosignanI P et al. Hum Reprod Update 2006; 12: 179–189. Reduction of serum estrogen levels Immunomodulatory effect Anti-inflammatory effect Decidualization + atrophy of endometrial tissue Inhibition of matrix metalloproteinases Anti-angiogenic effect Progestins
  15. 15. What is Dienogest? • Dienogest’s special chemical structure is responsible for it’s unique pharmacological profile Page 15 Properties of 19-nortestosterone derivatives • Strong progestational effect on endometrium • Relatively short plasma half-life of 9–11 hours • High oral bioavailability >90% Properties of progesterone derivatives • Good tolerability • Anti-androgenic effects • Relatively moderate inhibition of gonadotropin secretion • Mainly peripheral action Additional double bond (Strong affinity to progesterone receptors) Cyanomethyl instead of an ethinyl group in the 17α position (Low interaction with hepatic proteins e.g Cytochrome P450) Sasagawa S et al. Steroids 2008; 73: 222–231. Ruan X et al. Maturitas 2012; 71: 337–344.
  16. 16. Dienogest: Comparison with other Progestins Page 16 * Relative to other progestins Schindler AE, et al. Maturitas 2003; 46(Suppl 1): S7–S16. Krattenmacher R. Contraception 2000; 62(1): 29–38. Dienogest has properties that make it particularly suitable in endometriosis treatment*
  17. 17. Dienogest: Mechanism of Action in Endometriosis – Central effects (At level of hypothalamus & pituitary): • Inhibition of gonadotropin secretion: hypoestrogenic, hypergestrogenic endocrine environment1,2 with moderate suppression of circulating estradiol3 • Ovarian function: anovulation (2mg dose)3 – Local effects (At level of endometrial tissue) • Anti-Proliferative: inhibitory effect on proliferation of endometrial-like tissue4–6 • Anti-Inflammatory: impact on endometriosis-related inflammatory mediators7,8 • Anti-Angiogenenic: supressed angiogenesis in animal models of endometriosis9–11 • Modulation of prostaglandin E2 expression12,13 Page 17 Hypothalamus Pituitary gland Gonadotropins Estrogen and progesterone Negative feedback Uterus Ovary Estrogen Progesterone Endometrium 1. McCormack PL. Drugs 2010; 2. Sasagawa S et al. Steroids 2008; 3. Klipping C et al. J Clin Pharmacol 2012; 4. Katsuki Y et al. Eur J Endocrinol 1998; 5. Fischer OM et al. Gynecol Obstet Invest 2011; 6. Shimizu Y et al. Steroids 2011; 7. Horie S et al. Fertil Steril 2005; 8. Mita S et al. Fertil Steril 2011; 9. May K and Becker CM. Minerva Ginecol 2008; 10. Katayama H et al. Hum Reprod 2010; 11. Nakamura M et al. Eur J Pharmacol 1999; 12. Sacco K et al. Gynecol Endocrinol 2012; 13. Becker CM and D’Amato RJ. Microvasc Res 2007. Growth of endometrial lesions inhibited via both, central and local effects
  18. 18. 2. What’s New in Endometriosis
  19. 19. 2. What’s New in Endometriosis • Role of Estrogen in Endometriosis
  20. 20. Role of Estrogen in Endometriosis Page 20 Estrogens are responsible for proliferation of endometriotic tissue!
  21. 21. Role of Estrogen in Endometriosis Page 21 • Series of chemical reactions convert cholesterol to estradiol • The final step involves conversion of testosterone to estradiol • This is mediated by the enzyme: estradiol synthase or aromatase • 17β-HSD2 then degrades excess estradiol in to estrone (inactive form)
  22. 22. Growth and survival of the endometriotic lesions is favored due to the increased level of estrogen, locally Page 22 Testosterone Estradiol Estrone (weak, inactive form) Aromatase 17β-HSD2 Endometriosis High levels of Aromatase in endometriotic deposits Low levels of 17β-HSD2 in endometriotic deposits Normal Pathway
  23. 23. The Estrogen Threshold Theory Page 23 pg/mL Optimum Range where Endometriotic lesion growth and bone loss are minimized 100 10 Maximalresponse(%) 80 60 40 20 0 0 20 30 40 50 60 70 80 90 100 Atrophy of endometrial lesions Stimulation of endometrial lesions Substantial bone loss Minimal bone loss Endometrial lesion growth Bone turnover Reduction in estradiol levels below this curve results in a negative impact on bone turn-over – loss of bone mineral density & risk of osteoporosis! Increase in estradiol levels beyond this curve promotes endometrial lesion growth Mean estradiol levels with dienogest 2mg were 39pg/mL1 Estradiol concentration (pg/mL) Estradiol levels remain in the optimum range during treatment with Dienogest Figure adapted from Barbieri RL. J Reprod Med 1998; 43(3 Suppl): 287–292. Klipping C et al. J Clin Pharmacol 2012; 52: 1704–1713.
  24. 24. Use of CoCs in Endometriosis: But isn’t Endometriosis an estrogen-dependent, chronic inflammatory disease?? Page 24* CoCs: Combined Oral Contraceptives
  25. 25. Progestin-only pills are better first-line treatment for Endometriosis than CoCs! Pain improvement with CoCs may be attributed to the reduction of primary dysmenorrhea (PG-related), which may still occur in women with endometriosis Studies show lack of any beneficial effect of the OCP on non- menstrual pelvic pain and dyspareunia in these endometriosis patients Dose of Estrogen in low-dose CoCs is equivalent to 4 to 6 times the physiologic dose of estrogen In evidence of ER and PR alterations in endometriosis administering a high dose of estrogen and progestin in a CoC is counterproductive, resulting in estrogen dominance in the presence of progesterone resistance Casper RF. Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive Page 25 * ER: Estrogen Receptor; PR: Progesterone Receptor; CoCs: Combined Oral Contraceptives
  26. 26. 2. What’s New in Endometriosis • Diagnosis & • Management
  27. 27. Is surgical diagnosis of Endometriosis always necessary? Page 27
  28. 28. Goals of Management in Endometriosis Page 28 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 The Practice Committee of the American Society for Reproductive Medicine. Fertil Steril, 2014. 101(4): 927-35.
  29. 29. Role of progestins in Management of Endometriosis ESHRE, European Society of Human Reproduction and Embryology; WES, World Endometriosis Society; RCT, Randomly controlled trial 1. ESHRE 2013 guidelines; Accessed at: http://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline.aspx. 2. Johnson NP et al. Hum Reprod 2013; 28: 1552–1568. ESHRE guidelines: “Clinicians are recommended to use progestagens … as one of the options, to reduce endometriosis-associated pain”1 WES consensus: “Progestins with a proven effect in RCTs and with a specific indication for the treatment of endometriosis … can also be considered as first-line treatments”2 Progestins are recommended, gaining popularity, and are efficacious in treating the symptoms of endometriosis Newer progestins such as dienogest should be considered for use as first-line empirical medical treatment2
  30. 30. 2. What’s New in Endometriosis • Dienogest – A Unique Progestin
  31. 31. Estradiol levels during Dienogest treatment remain within suggested therapeutic window Page 31 Klipping C et al. J Clin Pharmacol 2012; 52: 1704–1713. Barbieri RL. J Reprod Med 1998; 43: 287–292.
  32. 32. Local effects of Dienogest: Suggested effects on Progesterone resistance! • Dienogest increased PR-B/PR-A ratio* PR-B activates progesterone genes/ PR-A represses PR-B • Dienogest decreased ERβ/ERα ratio* • Effects NOT seen with leuprolide acetate (LA) Hayashi A et al. J Ovarian Res 2012; 5(1): 31. * Relative to control in endometrial tissue ER= Estrogen receptor; PR= Progesterone receptor PR-B PR-A ERβERα Dienogest may help to improve progesterone resistance in endometriosis The resistance of endometriotic tissue to progesterone can be explained by alterations in the distribution of PR and ER isoforms Decreased PR-B/PR-A and increased ERβ/ERαratios have been demonstrated in endometriosis
  33. 33. Anti-inflammatory effect of Dienogest Shimizu Y et al. Steroids 2011; 76(1–2): 60–67. Horie S et al. Fertil Steril 2005; 83(5): 1530–1535. E2=estradiol; IL-8=interleukin-8; NF-κB=nuclear factor kappa B; TNFα=tumor necrosis factor α; DNG=dienogest. Cyclooxygenase-2 (COX-2)* Prostaglandin E2 (PGE2) Aromatase Local Estradiol Microsomal PGE2 synthase -1 (mPGES-1)* NF-B PGE2 synthases * Abundant expression in human endometrial epithelial cells TNFα IL-8 Endometriosis proliferation Inflammation DNG directly blocks the proliferation pathway in two ways: 1. Direct inhibition of NF-κB 2. Direct inhibition of estradiol in the ovary DNG DNG DNG DNG Prostaglandin E2 (PGE2)
  34. 34. 3. Clinical Discussions in Managing Endometriosis
  35. 35. 4. Newer Evidences on Dienogest Long-term Use of Dienogest in Endometriosis
  36. 36. VISADO (VISANNE STUDY TO ASSESS SAFETY IN ADOLESCENTS) A CLINICAL INVESTIGATION WITH DIENOGEST 2 MG/DAY IN ADOLESCENT PATIENTS Conclusion : SAFE..IN 5 YEARS FOLLOW UP
  37. 37. Conclusion – Mean lumbar spine BMD decrease (L2–L4) of 1.2% in adolescents after 1 year of treatment; partial recovery after cessation of treatment – Endometriosis-associated pain reduced in adolescents from a baseline value of 64.3 mm to a mean value of 9.0 mm on the VAS after 48 weeks • BMD: Bone mineral density, VAS: Visual analogue scale • Ebert AD et al. J Pediatr Adolesc Gynecol. 2017, doi: 10.1016/j.jpag.2017.01.014. In the adolescent endometriosis population the benefit-risk balance for Dienogest (2mg/d), especially in the light of a lack of alternative treatment options with a better benefit-risk profile, is considered favorable
  38. 38. International journal of women’s Health SAFETY & TOLERABILITY OF DIENOGEST IN ENDOMETRIOSIS : pooled analysis from the European clinical study program
  39. 39. CONCLUSION of study In this pooled analysis of 332 women with endometriosis , dienogest was well Tolerated with a favorable safety profile extending over period of up to 65 weeks. There is a paucity of randomized trial evidence to support the use of many treatment in endometriosis. These pooled analyses from four clinical trials of dienogest 2mg represent a contribution to evidence – based medicine in endometriosis, providing outcome of potential relevance to daily practice. • Bayer Holding 4:3 Template 2010 • July 2015
  40. 40. ADDRESS 11 Gagan Vihar, Near Karkari Morh Flyover, Delhi - 51 CONTACT US 9650588339 9599044257 011-22414049 WEBSITE : www.lifecareivf.in www.lifecarecentre.in www.lifecareabs.in ISO 14001:2004 (EMS) …..Caring hearts, healing hands ISO 9001:2008 Helpline : 9599044257 Web.www.lifecareivf.in Helpline : 9910081484 27 Year In your service
  41. 41. Thank you!

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