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

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. 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 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. 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
Percent of newborns with malformations

8. 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

9. 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%)

10. 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

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

12. 15th Jan 2017
Ban On Letrozole Lifted After 5 Long Years By DCGI

13. 13

14. 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)]

15. Current Clinical Guidelines

16. 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

17. 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.

19.  CC should be first-line pharmacotherapy for ovulation induction and letrozole can also be
used as first-line therapy.

20. Letrozole as
Ovulation
Inducer

21. 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.

22. 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.

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

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

25. 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.

27. 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

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
Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013

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
CC → No feedback inhibition
Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013

30. 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

31. 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

32. 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

33. 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

34. Letrozole vs CC

35. 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

36. 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

37. 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

38. Clomiphene citrate vs Letrozole

39. 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

40. Letrozole for OI in polycystic ovary
syndrome (PCOS)
Clinical Evidence

41. 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.

42. 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

43.  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

44. 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

45.  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

46.  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

47. Results
Ovulation rate and Clinical Pregnancy Rates

48. Other parameters

49. 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

50. 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.

51. 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.

52.  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).

53.  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.

54. Letrozole for OI in intrauterine
insemination (IUI)
Clinical Evidence

55.  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

56. 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.

57. 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

58.  Letrozole for OI in In Vitro
Fertilization (IVF)
Clinical Evidence

59. RCTs regarding use of letrozole for ovulation induction in
IVF/ICSI cycles
Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013

60. 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

61. 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