1. Letrozole 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
Behala Balananda Brahmachary Hospital, Kolkata
Techno India Hospital, Kolkata
Secretary, Perinatology Committee: Bengal Obstetric and Gynaecological Society (BOGS)
Managing Committee Member: BOGS
East Zone Representative, FOGSI Youth Cell (FOGSI Future)
15 Publications: National and International Journals

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.

5. Incidence of all malformations was not different between
the two groups (p= 0.25, 95%CI ).
However, the incidence of locomotor malformations (p= , 95% CI ) and cardiac anomalies (p= % CI ) were higher than in the control groups

6. 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 6

7. Number of newborns with major malformations
Percent of newborns with malformations 7

8. Hum Reprod Jan;32(1):

9. Reduces risk of miscarriage Safer option for mild ovarian stimulation
Conclusions
LTZ stimulation
Reduces risk of miscarriage
Safer option for mild ovarian stimulation
No increase in risk of
Major congenital anomalies
Adverse pregnancy outcomes
Adverse neonatal outcomes

10. Sharma S, et al. PLoS ONE. 2014; 9(10): e108219
Structural malformations & chromosomal abnormalities
Natural conception group
5 / 171 babies
(2.9%)
LTZ group
5 / 201 babies
(2.5%)
CC group
10 / 251 babies
(3.9%)

11. Other Studies Reference No of patients
Forman R, et al. J Obstet Gynaecol Can 2007;29:
430
Dehbashi S, et al. Iran J Med Sci 2009;34:23-8.
100
Legro RS, et al. N Engl J Med Jul 10;371(2):
750
Banerjee Ray P, et al. Arch Gynecol Obstet Mar;285(3):873-7.
147
Roy KK, et al. J Hum Reprod Sci Jan-Apr; 5(1): 20–25
204
Wu XK, et al. Fertil Steril 2016;106:
644
Requena A, et al. Hum Reprod Update Nov-Dec;14(6): (Meta-analysis)
2573
Diamond MP, et al. N Engl J Med 2015;373:
900

12. Wang R, et al. BMJ. 2017; 356: j138.

14. Letrozole as Ovulation Inducer

15. Causes of Subfertility
NICE Guidelines. Fertility Problems: Assessment and Treatment nice.org.uk/guidance/cg156

16. WHO Classification of AnovulationE2
FSH
Cause %
Type I ↓
Hypothalamo-Pituitary Failure
1-2
Type II
↑/ Normal
Normal,
high LH
Hypothalamo-Pituitary Dysfucntion
(Predominantly PCOS)
>90
Type III ↑
Ovarian Failure 10

17. Follicular Physiology
Exogenous FSH
granulosa cells
FSH
aromatase
CC binds to ER & depletes receptor concentrations
estrogen LH
theca cells
androstenedione
Aromatase
aromatase inhibition 20

18. Management of PCOS-Anovulation
Life Style Modification CC
1st Line Treatment
No Ovulation (CC Resistance)
Metformin + CC
FSH
Lap Ovarian Drilling
Letrozole
Ovulates

19. Management of PCOS-Anovulation
Life Style Modification CC
1st Line Treatment
No Ovulation (CC Resistance)
Metformin + CC
FSH
Lap Ovarian Drilling
Letrozole
Ovulates

20. Clomiphene Citrate 1st line treatment for OI for >55 yrs
Ovulation: 60-85% cases
About 20-25% of anovulatory women are CC-resistant
Pregnancy rate: 10-20%/cycle
Failure of 6 CC cycles: Other factors for infertility should be considered
Effective & safe oral agent
Thins out endometrium, reduces cervical secretion
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: ; Banerjee Ray P, et al. Arch Gynecol Obstet Mar;285(3):873-7.; Pavone ME, et al. J Clin Endocrinol Metab May; 98(5): 1838–1844. 23

21. Letrozole 3rd generation aromatase inhibitor (AI)
Non-steroidal, potent & selective
1st study (Mitwally & Casper, 2001): OI
Mitwally MF, et al. Fertil Steril Feb;75(2):305-9.

22. Concept study: Letrozole for OI25

23. Endometrial thickness & E2 levels
In anovulatory patients with PCOS
Variable
LTZ treatment
CC treatment
P value
ET (mm)
8.1 ± 1.4
6.2 ± 2.5
<0.01
E2 levels on day of hCG (pmol/L)
962 ± 654
1638 ± 1406
In ovulatory patients
Variable
LTZ treatment
CC treatment
P value
ET (mm)
8.9 ± 1.2
5.0 ± 1.0
<0.001
E2 levels on day of hCG (pmol/L)
719 ± 411
3003 ± 1422 26

24. Concept study: Conclusions
Mitwally MF, et al. Fertil Steril Feb;75(2):305-9. 27

25. Letrozole vs CC
Legro RS, et al. N Engl J Med Jul 10;371(2):
Ovulation, Pregnancy, and Live Birth rates- all were significantly better in Letrozole group, in women with normal and with high BMI
Banerjee Ray P, et al. Arch Gynecol Obstet Mar;285(3):873
Pregnancy rate and Live birth rates were better in letrozole group
Roy KK, et al. J Hum Reprod Sci Jan-Apr; 5(1): 20–25.
Miscarriage rates were similar than CC
Multiple pregnancy rates higher with CC
Letrozole may be considered as the 1st line of agent for OI
-7.

26. Roque M, et al. Gynecol Endocrinol. 2015;31(12):917-21

27. Primary outcome: LBR
Roque M, et al. Gynecol Endocrinol. 2015;31(12):917-21

28. Secondary outcome: Pregnancy rate
Roque M, et al. Gynecol Endocrinol. 2015;31(12):917-21

29. Secondary outcomes: Others
No statistically significant difference between LTZ & CC groups in…
Ovulation rate per cycle
RR=1.15; 95% CI: 0.98–1.34
Multiple pregnancy rates
RR=0.43; 95% CI: 0.17–1.06
Miscarriage rate
RR=1.43; 95% CI: 0.98–2.06

30. Conclusion
LTZ is superior to CC considering live birth & pregnancy rates in patients with PCOS

31. 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:

32. 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):

33. Letrozole plus Gn in CC-resistant infertile women with PCOS
Xi W, et al. Drug Des Devel Ther. 2015; 9: 6001–6008.

34. Conclusion LTZ in combination with HMG
Reduce risks of OHSS in CC-resistant women with PCOS
More appropriate in patients sensitive to gonadotropin

35. Guidelines
Society
Year
Recommendation
ACOG
2016
Letrozole- 1st-line therapy for PCOS & BMI > 30
WHO
CC or Letrozole
Australian National Health and Medical Research Council (NHMRC) guideline
2015
American Association of Clinical Endocrinologists, American College of Endocrinology,
Androgen Excess and PCOS Society
Endocrine Society
2013

36. Pharmacology Parameter Data Absorption
Rapid & complete (Cmax within 1 h)
Bioavailability
99.9%
Food
Absorption not affected by food
Metabolism
Inactive metabolite, by CYP 2A6 & 3A4
Elimination T1/2
~2 days (45 h)
Excretion
Renal (90%), rapid clearance, no accumulation
Safety
Well tolerated
Prescribing information; Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: ; Harriet et al. Drugs 1998; 56(6): ; Bhatnagar AS. Breast Cancer Res Treat 2007;105:7–17 40

37. Dose, Duration, Monitoring
hCG 10,000 IU IM
(follicle ≥18 mm/; ET > 7 mm)
Menses 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 … 28
Timed intercourse/ IUI h after hCG administration
LTZ 2.5 mg/d
TVS Monitoring
Ovulation
Dose >2.5 mg/ d and more than 3 cycles is not recommended
TVS Monitoring is recommended at least in 1st cycle

38. Advantages of letrozole over CC
Parameters
Clomiphene citrate
Letrozole
MOA
SERM
Aromatase inhibitor
Half-life
Long, 5-7 days
Short, 45 h
Anti-estrogenic effects
Thin endometrium & altered cervical mucus
Thick endometrium & favourable cervical mucus
Uterine blood flow
Decreased
Increased
OHSS risk
High
Low
Multiple pregnancy
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91:

39. Summary
Better pregnancy outcomes & higher live births compared to CC in PCOS patients
Effective even in patients with CC-resistant PCOS
Reduces Gn dose & superior alternative to CC in combined Gn cycles
Monofollicular development & lower multiple pregnancies
No anti-estrogenic effects on endometrium & cervical mucus
Lower cycle cancellation & risk of hyperstimulation
Safety established in clinical studies

40. Thank You