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Letrozole in Ovulation Induction

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Invited Lecture Delivered by Dr Sujoy Dasgupta in a CME by Encure Pharma at Kolkata, May, 2017

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Letrozole in Ovulation Induction

  1. 1. Induz in Ovulation Induction Dr Sujoy Dasgupta MBBS (Gold Medalist, Hons) MS (Obst & Gynae- Gold Medalist) DNB, FIAOG, Fellow- Reproductive Endocrinology and Infertility (ACOG, USA) Assistant Professor: SRIMSH, Durgapur Consultant: RSV Hospital, Kolkata Iris Hospital, Kolkata Behala Balananda Brahmachary Hospital, Kolkata Secretary, Perinatology Committee: Bengal Obstetric and Gynaecological Society (BOGS)- 2016-17 Managing Committee Member: BOGS- 2016-17 15 Publications: National and International Journals
  2. 2. NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources.
  3. 3. Incidence of all malformations was not different between the two groups (p= 0.25, 95%CI 0.78-4.71). However, the incidence of locomotor malformations (p= 0.0005, 95% CI 2.64-27.0) and cardiac anomalies (p= 0.0006 95% CI 3.30-58.1) were higher than in the control groups
  4. 4. Fertil Steril. 2006 Jun;85(6):1761-5  No difference in overall rates of major & minor congenital malformations among newborns from mothers who conceived after LTZ or CC treatments  It appears that congenital cardiac anomalies are less frequent in LTZ group  The concern that LTZ use for ovulation induction could be teratogenic is unfounded based on this data
  5. 5. Number of newborns with major malformations Percent of newborns with malformations
  6. 6. Hum Reprod. 2017 Jan;32(1):125-132 N= 3928 LTZ stimulation reduces risk of miscarriage, with no increase in risk of major congenital anomalies or adverse pregnancy
  7. 7. Sharma S, et al. PLoS ONE. 2014; 9(10): e108219 Structural malformations & chromosomal abnormalities N= 623 Natural conception group 5 / 171 babies (2.9%) LTZ group 5 / 201 babies (2.5%) CC group 10 / 251 babies (3.9%)
  8. 8. Other Studies Reference No of patients Forman R, et al. J Obstet Gynaecol Can 2007;29:668-71. 430 Dehbashi S, et al. Iran J Med Sci 2009;34:23-8. 100 Legro RS, et al. N Engl J Med. 2014 Jul 10;371(2):119-29. 750 Banerjee Ray P, et al. Arch Gynecol Obstet. 2012 Mar;285(3):873-7. 147 Roy KK, et al. J Hum Reprod Sci. 2012 Jan-Apr; 5(1): 20–25 204 Wu XK, et al. Fertil Steril 2016;106:757-765 644 Requena A, et al. Hum Reprod Update. 2008 Nov-Dec;14(6):571-82. (Meta-analysis) 2573 Diamond MP, et al. N Engl J Med 2015;373:1230-40. 900
  9. 9. Wang R, et al. BMJ. 2017; 356: j138.
  10. 10. 15th Jan 2017 Ban On Letrozole Lifted After 5 Long Years By DCGI
  11. 11. 13
  12. 12. Letrozole Revoked MINISTRY OF HEALTH AND FAMILY WELFARE [(Department of Health and Family Welfare) NOTIFICATION: New Delhi, the 17th February, 2017 G.S.R. 145(E)]
  13. 13. Current Clinical Guidelines
  14. 14. For women with PCOS and BMI >30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate
  15. 15. Endocrine Society Clinical Guideline (2013) recommends:  Clomiphene citrate (or comparable estrogen modulators such as Letrozole) as the first-line treatment of anovulatory infertility in women with PCOS. American Association of Clinical Endocrinologists, American College of Endocrinology, And Androgen Excess & PCOS Society (2015)  Treatment for women with PCOS and anovulatory infertility should begin with an oral agent such as clomiphene citrate or Letrozole, an aromatase inhibitor.
  16. 16.  CC should be first-line pharmacotherapy for ovulation induction and letrozole can also be used as first-line therapy.
  17. 17. Letrozole as Ovulation Inducer
  18. 18. Clomiphene Citrate  Ovulation: 70-80% cases  Pregnancy rate: 10-20%/cycle* not more then 6 cycle continuously and not more then 12 cycles in life time ..to avoid possible Risk of (?) Ovarian Malignancy (NICE, 2013) In doses of 50 mg/d /cycle and can be increased to 150 mg until ovulation is achieved *Pavone ME, et al. J Clin Endocrinol Metab. 2013 May; 98(5): 1838–1844.
  19. 19. CC Resistance/ Failure  CC RESISTANT: If patient fails to ovulate despite 3 CC cycles  About 20-25% of Anovulatory women are CC- resistant*  CC FAILURE:  CC-resistant  women who ovulate, but do not get pregnant  Women who get pregnant but end in miscarriage *Mitwally MF, et al. Fertil Steril. 2001 Feb;75(2):305-9, Azargoon A, et al. Iran J Reprod Med. 2012 Jan; 10(1): 33–40.
  20. 20. Management of PCOS-Anovulation Life Style Modification CC 1st Line Treatment No Ovulation (CC Resistance) Metformin + CC FSH Lap Ovarian Drilling Letrozole Ovulates
  21. 21. Management of PCOS-Anovulation Life Style Modification CC 1st Line Treatment No Ovulation (CC Resistance) Metformin + CC FSH Lap Ovarian Drilling Letrozole Ovulates
  22. 22. Letrozole 3rd generation aromatase inhibitor (AI) Non-steroidal, potent & selective 1st study (Mitwally & Casper, 2001): OI Mitwally MF, et al. Fertil Steril. 2001 Feb;75(2):305-9.
  23. 23. granulosa cells FSH aromatase LH theca cells androstenedione estrogen Follicular Physiology Aromatase 1. Ovary 2. Adipose tissue 3. Brain Exogenous FSH CC binds to ER & depletes receptor concentrations aromatase inhibitors
  24. 24. Follicular Development Pituitary gland FSH Stimulates follicular growth Estrogen Large follicles (more FSH receptors) Smaller follicles (less FSH receptors) Continues to grow (mono follicular) Atresia Ovulation Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013
  25. 25. Follicular Development Pituitary gland FSH Stimulates follicular growth Estrogen Large follicles (more FSH receptors) Smaller follicles (less FSH receptors) Continues to grow (mono follicular) Atresia Ovulation CC → No feedback inhibition Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013
  26. 26. Follicular Development Pituitary gland FSH Stimulates follicular growth Estrogen Large follicles (more FSH receptors) Smaller follicles (less FSH receptors) Continues to grow (mono follicular) Atresia Ovulation CC → No feedback inhibition Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013
  27. 27. Follicular Development Pituitary gland FSH Stimulates follicular growth Estrogen Follicles with FSH receptors Smaller follicles (less FSH receptors) Continues to grow (multi follicular) Atresia Ovulation CC → No feedback inhibition Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013
  28. 28. Follicular Development Pituitary gland FSH Stimulates follicular growth Estrogen Large follicles (more FSH receptors) Smaller follicles (less FSH receptors) Continues to grow (mono follicular) Atresia Ovulation Letrozole → maintains feedback inhibition Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013
  29. 29. Follicular Development Pituitary gland FSH Stimulates follicular growth Estrogen Large follicles (more FSH receptors) Smaller follicles (less FSH receptors) Continues to grow (mono follicular) Atresia Ovulation Letrozole → maintains feedback inhibition Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013
  30. 30. Letrozole vs CC
  31. 31. Letrozole vs CC Letrozole (Aromatase Inhibitor) Blocks Aromatase Does not block ER Increased intraovarian androgen 1. No adverse effect on endometrium/ cervix Augment FSH receptors Stimulates IGF-I 2. No hot flush Synergistically promotes follicular growth Clomiphene (Anti-estrogen) Blocks ER 1. ↓ endometrial thickness ↓glandular density ↓ uterine blood flow in luteal phase 2. ↓quantity/ quality of Cx mucus 3. Hot flushes (prolonged accumulation in tissues→ prolonged depletion of ER) J Clin Endocrinol Metab, March 2006, 91(3):760 –771 J Hum Reprod Sci 2011 May-Aug; 4(2): 76–79. J Hum Reprod Sci 2013 Apr-Jun; 6(2): 93–98
  32. 32. Letrozole vs CC Letrozole (Aromatase Inhibitor) Blocks Aromatase Does not block ER Increased intraovarian androgen 1. No adverse effect on endometrium/ cervix Augment FSH receptors Stimulates IGF-I 2. No hot flush Synergistically promotes follicular growth Clomiphene (Anti-estrogen) Blocks ER 1. ↓ endometrial thickness ↓glandular density ↓ uterine blood flow in luteal phase 2. ↓quantity/ quality of Cx mucus 3. Hot flushes (prolonged accumulation in tissues→ prolonged depletion of ER) J Clin Endocrinol Metab, March 2006, 91(3):760 –771 J Hum Reprod Sci 2011 May-Aug; 4(2): 76–79. J Hum Reprod Sci 2013 Apr-Jun; 6(2): 93–98
  33. 33. Letrozole vs CC Letrozole (Aromatase Inhibitor) Blocks Aromatase Does not block ER Increased intraovarian androgen 1. No adverse effect on endometrium/ cervix Augment FSH receptors Stimulates IGF-I 2. No hot flush Synergistically promotes follicular growth Clomiphene (Anti-estrogen) Blocks ER 1. ↓ endometrial thickness ↓glandular density ↓ uterine blood flow in luteal phase 2. ↓quantity/ quality of Cx mucus 3. Hot flushes (prolonged accumulation in tissues→ prolonged depletion of ER) J Clin Endocrinol Metab, March 2006, 91(3):760 –771 J Hum Reprod Sci 2011 May-Aug; 4(2): 76–79. J Hum Reprod Sci 2013 Apr-Jun; 6(2): 93–98
  34. 34. Clomiphene citrate vs Letrozole
  35. 35. Letrozole Uses  Letrozole has been used in the following three situations:  OI in polycystic ovary syndrome (PCOS)  OI in intrauterine insemination (IUI)  Ovarian stimulation for IVF/ICSI
  36. 36. Letrozole for OI in polycystic ovary syndrome (PCOS) Clinical Evidence
  37. 37. CONCLUSION: letrozole showed a better endometrial response and pregnancy rate compared to CC Endometrial thickness on the day of hCG administration (mm) 9.1±0.3 6.3±1.1 0.014 (S) Roy KK, et al. J Hum Reprod Sci. 2012 Jan-Apr; 5(1): 20–25.
  38. 38. Population Studied 7 studies out of 232 selected • N= 1833 patients – LTZ: 906 – CC: 927 • N= 4999 ovulation cycles – LTZ: 2455 – CC: 2544 OUTCOME MEASURES  Primary outcome measure: Live birth rate (LBR)  Secondary outcomes measures: Ovulation rate per cycle Clinical pregnancy rate Miscarriage rate Multiple pregnancy rates
  39. 39.  Result  statistically significant increase in the live birth and pregnancy rates in the letrozole group when compared to the CC group  Conclusion  LTZ is superior to CC considering live birth & pregnancy rates in patients with PCOS
  40. 40. CC 100 mg for at least 6 cycles → failure to form the DF, then put on letrozole ; 5 mg for 5 days for 4 cycles → unable to form the DF, combination therapy (letrozole 5 mg + CC100 mg) for 5 days PCOS patients resistant to clomiphene and letrozole used alone as single agents, Letrozole with CC combination may be used as a first-line therapy to induce ovulation in severe cases of PCOS in order to save time and expense
  41. 41.  Statistically significantly increased the ovulation rate by 33.3% in the treatment group  letrozole can be used as an effective and simple alternate ovulation-inducing agent in these women Fertility and Sterility Vol. 94, No. 7, December 2010
  42. 42.  N=94 : letrozole ( 2.5 mg/day) + HMG,  N= 90: CC (50 mg/day) + HMG,  N=71: HMG only.  All women received one treatment regimen in one treatment cycle.  All patients were given HMG 75 IU on alternate days daily starting on day 3 or day 7 until the day of administration of hCG.  hCG 10,000 IU : when at least 1 follicle with mean diameter ≥18 mm  Pts advised natural intercourse after 24-36 hours after hCG
  43. 43. Results Ovulation rate and Clinical Pregnancy Rates
  44. 44. Other parameters
  45. 45. Conclusion Letrozole in combination with hMG reduced duration of stimulation and total HMG dose needed for stimulation significantly higher monofollicular development The regimen of letrozole + HMG is more effective and safer than CC + HMG or HMG alone for ovulation induction in cases of CC resistance
  46. 46. Letrozole vs. LOD in CC Failure LTZ had superior reproductive outcomes compared with LOD in women with CC-resistant PCOS LTZ could be used as 1st line treatment for women with CC-resistant PCOS Liu W, et al. Experimental and Therapeutic Medicine. 2015; 10: 1297-1302.
  47. 47. Comparison of Letrozole vs. Tamoxifen LTZ superior to TMX Higher pregnancy rate Higher ovulation rate El-Gharib et al. J Reprod Infertil. 2015; 16(1): 30-35.
  48. 48.  60 moderately obese patients with PCOS  N=31 clomiphene citrate-metformin  N=29 letrozole-metformin therapy.  Stimulation was carried out for the procedures of intrauterine insemination (IUI).
  49. 49.  60 moderately obese patients with PCOS  N=31 clomiphene citrate-metformin  N=29 letrozole-metformin therapy.  Stimulation was carried out for the procedures of intrauterine insemination (IUI).  RESULTS: 0 2 4 6 8 10 letrozole+metformin CC+metformin 8.9 6.3 EndometrialThickness(mm) 0 5 10 15 20 25 Letrozole+metformin CC+Metformin 20.6 9.6 PregnancyRateafterthirdIUI cycle(%) Fig : Showing Endometrial Thickness Fig : Preg Rate after third IUI cycle Conclusion: Study demonstrated the advantages of the use of letrozole over clomiphene citrate in combination with metformin in moderately obese patients with PCOS who are resistant to stimulation with clomiphene citrate alone.
  50. 50. Letrozole for OI in intrauterine insemination (IUI) Clinical Evidence
  51. 51.  Methods  group A :Letrozole (5 mg) for five days and gonadotrophins (HMG) 75 IU once daily for 3−5 days  group B : Clomiphene Citrate (50 mg) for 5 days and gonadotrophins (HMG) in a dose of 75 IU for 3– 5days  Results  Patients co-treated with Letrozole required fewer gonadotrophins administrations and had a thicker endometrium  The pregnancy rate was not significantly different between two groups (11% vs. 12.6%) J Reprod Infertil 2013 Jul-Sep; 14(3): 138–142. Conclusion: The addition of Letrozole to gonadotrophins decreases gonadotrophins requirements and improves endometrial thickness, without a significant effect on pregnancy rates
  52. 52. 180 infertile women:  Group A: 5 mg/day letrozole on day 3-7 of menstrual cycle.  Group B: 100 mg/day clomiphene in the same way as letrozole.  hMG administered in both groups every day starting on day between 6-8 of cycle.  hCG(5000 IU) trigger when have two follicles of ≥16 mm.  IUI was performed 36 hr later. Int J Reprod Biomed (Yazd).2017 Jan;15(1):49-54.
  53. 53. Results 0 5 10 Letrozole+ HMG CC+HMG 3.8 3.7 8.99 8.46 EndometrialThickness(mm) Fig 2: Showing Endometrial Thickness Before treatment After Treatment 0 2 4 6 Letrozole+ HMG CC+HMG 5.7 anHyperstimulation(%) Fig 3: Showing Ovarian Hyperstimulation 0 10 20 30 Letrozole+ HMG CC+HMG 26.51 12.64 ClinicalPregnancyRate(%) Fig 1: Showing Clinical Pregnancy Rate
  54. 54.  Letrozole for OI in In Vitro Fertilization (IVF) Clinical Evidence
  55. 55. RCTs regarding use of letrozole for ovulation induction in IVF/ICSI cycles Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013
  56. 56. Letrozole in IVF  Normal ovarian response  Addition of letrozole showed higher implantation and ongoing pregnancy rates and significantly improved endometrial thickness  Poor responders  Lower dose of gonadotropin required in the letrozole cotreatment group in all trials
  57. 57. Summary  Better pregnancy outcomes & higher live births compared to CC in PCOS patients  Effective even in patients with CC-resistant PCOS  Reduces Gonadotrophin dose & superior alternative to CC in combined Gonadotrophin cycles  Monofollicular development & lower multiple pregnancies  No anti-estrogenic effects on endometrium & cervical mucus  Lower cycle cancellation & risk of hyperstimulation is negligible  Safety established in clinical studies

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