Lecture Delivered by Dr Sujoy Dasgupta who was invited in a Scientific Session organized by Sun Pharma (Inca) at IMA Conference

1. Letrozole in Ovulation Induction
1
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)- 2016-17
Managing Committee Member: BOGS- 2016-17
East Zone Representative, FOGSI Youth Cell (FOGSI Future) 2017-18
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.
2

3. 3

4. 4

5. 5
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

6. 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

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

8. 8
Hum Reprod. 2017 Jan;32(1):125-132

9. LTZ
stimulation
Reduces risk of
miscarriage
No increase in risk of
Major congenital
anomalies
Adverse pregnancy
outcomes
Adverse neonatal
outcomes
Conclusions
11
Safer option for mild
ovarian stimulation

10. Sharma S, et al. PLoS ONE. 2014; 9(10): e108219
12
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;29:668-71. 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

12. Wang R, et al. BMJ. 2017; 356: j138.
15

13. 16

14. Letrozole as Ovulation
Inducer
17

15. Causes of Subfertility
Ovulatory
20%
Male Factor
30%
Tubal
25%
Unexplained
25%
18
NICE Guidelines. Fertility Problems: Assessment and Treatment
nice.org.uk/guidance/cg156

16. WHO Classification of Anovulation
E2 FSH Cause %
Type I ↓ ↓ Hypothalamo-Pituitary
Failure
1-2
Type II ↑/
Norm
al
Normal,
high LH
Hypothalamo-Pituitary
Dysfucntion
(Predominantly PCOS)
>90
Type III ↓ ↑ Ovarian Failure 10
19

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

18. Management of PCOS-Anovulation
Life Style Modification
CC
1st Line Treatment
No Ovulation (CC Resistance)
Metformin + CC FSH Lap Ovarian Drilling Letrozole
Ovulates
21

19. Management of PCOS-Anovulation
Life Style Modification
CC
1st Line Treatment
No Ovulation (CC Resistance)
Metformin + CC FSH Lap Ovarian Drilling Letrozole
Ovulates
22

20.  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
23
Clomiphene Citrate
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.; Banerjee Ray P, et al. Arch Gynecol Obstet. 2012 Mar;285(3):873-7.;
Pavone ME, et al. J Clin Endocrinol Metab. 2013 May; 98(5): 1838–1844.

21. Letrozole
• 3rd generation aromatase inhibitor (AI)
• Non-steroidal, potent & selective
• 1st study (Mitwally & Casper, 2001): OI
24Mitwally MF, et al. Fertil Steril. 2001 Feb;75(2):305-9.

22. Concept study: Letrozole for OI
25

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 <0.01
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 <0.001
26

24. Concept study: Conclusions
Mitwally MF, et al. Fertil Steril. 2001 Feb;75(2):305-9.
27

25. Letrozole vs CC
Legro RS, et al. N Engl J Med. 2014
Jul 10;371(2):119-29.
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. 2012 Mar;285(3):873
Pregnancy rate and Live birth rates
were better in letrozole group
Roy KK, et al. J Hum Reprod Sci.
2012 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
28
-7.

26. Roque M, et al. Gynecol Endocrinol. 2015;31(12):917-21
29

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

28. Roque M, et al. Gynecol Endocrinol. 2015;31(12):917-21
Secondary outcome: Pregnancy
rate
32

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. LTZ is superior to CC considering live birth & pregnancy
rates in patients with PCOS
Conclusion
34

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: 1297-1302.
35

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): 30-35.
36

33. Letrozole plus Gn in CC-resistant
infertile women with PCOS
Xi W, et al. Drug Des Devel Ther. 2015; 9: 6001–6008.
37

34. Conclusion
LTZ in
combination with
HMG
Reduce risks of OHSS in CC-
resistant women with PCOS
More appropriate in patients
sensitive to gonadotropin
38

35. Guidelines
Society Year Recommendation
ACOG 2016 Letrozole- 1st-line therapy for PCOS &
BMI > 30
WHO 2016 CC or Letrozole
Australian National Health and
Medical Research Council
(NHMRC) guideline
2015 CC or Letrozole
American Association of
Clinical Endocrinologists,
American College of
Endocrinology,
Androgen Excess and PCOS
Society
2015 CC or Letrozole
Endocrine Society 2013 CC or Letrozole
39

36. Prescribing information; Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771; Harriet et al. Drugs 1998; 56(6):1125-1140;
Bhatnagar AS. Breast Cancer Res Treat 2007;105:7–17
Pharmacology
40
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

37. Dose, Duration, Monitoring
Ovulation
Menses
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 … 28
LTZ 2.5 mg/d
hCG 10,000 IU IM
(follicle ≥18 mm/; ET > 7 mm)
Timed intercourse/ IUI
24-36 h after hCG
administration
41
Dose >2.5 mg/ d and
more than 3 cycles is
not recommended
TVS Monitoring
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 High Low
42
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

39. Summary
43
 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