why to use aromatiase inhoiibitors in gynecology

1. Letrozole & Reproduction
DR.HESHAM AL-INANY

2. Why Do We Need This Talk
 To update our knowledge and understanding
 To provide evidence for decision-makers
 To provide our patients with best care based on Evidence
2

3. Outline
 Introduction
 PCOS
 Unexplained infertility
 Fertility preservation for breast cancer
 Frozen embryo transfer
 Decreases OHSS

4. WHO Groups I to III
4
FSH usually
normal
FSH
usually
high
Hypothalamic
pituitary
dysfunction
(often PCOS)
Ovarian failure
Hypothalamic
pituitary failure
(hypogonadotrophi
c hypogonadism)
Group III 10%
Group II >85%
Group I : <5%
Normal
estrogen and
prolactin
1.World Health Organization. World Health Organ Tech Rep Ser. 1973;514:1–30.
2.Casper et al. J Clin Endocrinol Metabol. 2006;91(3):760–771.
FSH usually
low
Estrogen
deficient and
low prolactin

5. Overcoming Infertility: Group I
OI can be achieved by2
Gn
5
FSH usually
low
Hypothalamic pituitary failure
(hypogonadotrophic hypogonadism)
Group I1
Low
Estrogen
Low
prolactin
1.Casper et al. J Clin Endocrinol Metabol. 2006;91(3):760–771.
2.Messinis. Hum Reprod. 2005;20(10):2688–2697.

6. Overcoming Infertility: Group II
6
1. Casper et al. J Clin Endocrinol Metabol. 2006;91(3):760–771.
2. Messinis. Hum Reprod. 2005;20(10):2688–2697.
FSH usually
normal
Hypothalamic pituitary dysfunction
(often PCOS)
Group II1
Normal
estrogen
Normal
prolactin
OI can be achieved by :
(clomiphene citrate)
Aromatase
inhibitors Gn Metformin LOD

7. Oral drugs
Aromatase Inhibitors
: Decrease the
aromatization of
androgens to
estrogens, releasing
the hypothalamic–
pituitary axis from
negative feedback of
estrogen.

8. advantages in ovulation induction
1. It does not deplete ERs throughout the body
2. It keeps the hypo-thalamo-pituitary axis intact
3. It is short acting (48 hr. half-life).
This ensures improved endometrial thickness, cervical mucus, mono-follicular,
and better folliculogenesis which lead to higher pregnancy rates and singleton
pregnancy rates.

9. RCT Anatomy
Participants
R
a
n
d
o
m
l
y
A
s
s
i
g
n
e
d
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
O
u
t
c
o
m
e
C
o
m
p
a
r
e
d

10. Meta-analysis

11. Outline
 Introduction
 PCOS
 Unexplained infertility
 Fertility preservation for breast cancer
 Frozen embryo transfer
 Decreases OHSS

12. Letrozole versus Clomiphene for Infertility in the Polycystic
Ovary Syndrome Legro, R.S. et al., 2014
The new England journal o f medicine, 2014
Study design
• Double-blind, multicenter trial,
• randomly assigned 750 women 18 to 40 years of age with the polycystic ovary
syndrome, in a 1:1 ratio, to receive letrozole (2.5 mg daily) or clomiphene (50 mg daily)
with up titration for non responders with The maximum daily dose of clomiphene was
150 mg (three pills), and the maximum daily dose of letrozole was 7.5 mg (three pills)
for five days for up to five treatment cycles.
• Modified Rotterdam criteria was used to diagnose the polycystic ovary syndrome

13. Primary out comes :Live birth
27.5
19.1
0
5
10
15
20
25
30
Letrozole 2.5 mg CC 50 mg
Live birth%
The cumulative live-birth rate is significantly higher with letrozole 27.5% than with
clomiphene Citrate 19.3% among women with the polycystic ovary syndrome
P value = 0.007

14. Live birth rate analysis according to maternal BMI
• For Females with BMI 30 and more “ obese”, Letrozole will be the effective oral ovulation
induction.
• Letrozole & CC have the same effect for females with BMI less 30

15. The ovulation rate was significantly higher with letrozole than with clomiphene at
each monthly visit (P<0.01 for all comparisons)
61.7
48.3
0
10
20
30
40
50
60
70
Letrozole 2.5 mg CC 50 mg
Ovulation rate%
Secondary out comes :Ovulation Rate
improves ovulation rate by 13.4% than CC
(P<0.01)

16. Meta-analysis

17. Traditional
MA results

18. Flowchart of studies included in
systematic and meta-analysis.
• MEDLINE, EMBASE, Scopus, Web
of Science, Cochrane Central
Register of Clinical. No language
restrictions were applied.
• All published trials studying the
impact of CC alone vs other drug
regimens on mid-cycle endometrial
thickness in women with WHO
group II ovulatory disorders were
searched for.

19. Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in
anovulatory women: systematic review and meta-analysis
Gadalla et al., UOG 2018
Results
Forest plot for comparison of live birth between CC and letrozole

20. Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in
anovulatory women: systematic review and meta-analysis
Gadalla et al., UOG 2018
Results
Forest plot for comparison of mid-cycle endometrial thickness
between CC and letrozole.

21. Franik S, eltrop SM, kremer JAM, kiesel L, farquhar C. Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. Cochrane database of systematic reviews 2018, issue 5. Art. No.: Cd010287.
 Letrozole appears to
improve live birth and
pregnancy rates in subfertile
women with anovulatory
polycystic ovary syndrome,
compared to clomiphene
citrate.
 There is high-quality
evidence that OHSS rates are
similar with Letrozole or
clomiphene citrate.
 There is high-quality
evidence of no difference in
miscarriage rates or multiple
pregnancy rates.
Favoring other OI agents Favoring LTZ

22. NATURE, 2017

23. Network Meta-analysis

24. Network Results

25. Letrozole can be recommended as first line treatment due to its higher ovulation,
pregnancy, and live birth rate as well as lower multiple pregnancy rate.

27. Induction of Ovulation
Oral Agents
Aromatase Inhibitors

29. In conclusion, our results of randomized trial suggest that
letrozole is as good as CC in terms of ovulation rate.
The endometrial thickness was significantly better in the
letrozole group.
letrozole is a safe and better alternative to CC in ovulation
induction protocol for patients of anovulatory PCOS, and it may
be considered as a first-line treatment for ovulation induction
in these patients.

30. 02
Letrozole does not increase the risk of major congenital anomalies or adverse pregnancy
or neonatal outcomes compared with natural cycles in patients undergoing ART

31. The cost per cycle was significantly lower in Group Let+FSH versus
Group FSH alone II (468.93 Can dollars +/- 418.18 versus 1067.28 +/-
921.43;
P < 0.0001).
Conclusion: A Letrozole-FSH combination could be an effective
ovarian stimulation protocol in IUI cycles.

32. Outline
 Introduction
 PCOS
 Unexplained infertility
 Fertility preservation for breast cancer
 Frozen embryo transfer
 Decreases OHSS

33. • Findings suggest LTZ is as effective as CC for
ovulation induction in couples with unexplained
infertility. However, LTZ appears to result in a
higher rate of clinical pregnancy per cycle at the
lowest starting dose of 2.5 mg.

36. Outline
 Introduction
 PCOS
 Unexplained infertility
 Fertility preservation for breast cancer
 Frozen embryo transfer
 Decreases OHSS

37.  Since two-thirds of breast cancers are estrogen positive and estrogen
promotes the growth of breast cancer cells, a major concern with
fertility preservation is the exposure of the patient to high doses of
estrogen, as is typical during a controlled ovarian hyperstimulation in
an ART setting. [1-2]
 Oktay et al. showed that concomitant treatment with Letrozole
during the controlled ovarian hyperstimulation could be used to
prevent high levels of estrogen production [3].
The Role Of Letrozole For Fertility Preservation in Breast
Cancer Patients
1-Huang WY, Newman B, Millikan RC, Schell MJ, Hulka BS, Moorman PG. Hormone-related factors and risk of breast cancer in relation to estrogen receptor and
progesterone receptor status. Am J Epidemiol. 2000;151:703–14.
2-Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advance breast cancer in
postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003;21:2101–9.
3-Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with
tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol. 2005;23:4347–53.

38. The Role Of Letrozole For Fertility Preservation in
Breast Cancer Patients
 Typically, Letrozole is started on day 2 or 3 of
the menstrual cycle and exogenous FSH is
administered starting 2 days later.
 Both are continued until oocyte maturity is
triggered with GnRH agonist instead of hCG.[1]
 Rodgers et al. summarized twelve studies using
this approach and found peak estradiol levels to
average 337–829 pg/ml, which is only slightly
higher than the peak estradiol levels found
during natural cycles [2].
 In spite of high doses of Letrozole, a pre-
menopausal woman still produces a significant
quantity of estradiol.
1-Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation
with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol. 2005;23:4347–53.
2- Rodgers RJ, Reid GD, Koch J, Deans R, Ledger WL, Friedlander M, et al. The safety and efficacy of controlled ovarian hyperstimulation for fertility preservation in
women with early breast cancer: a systematic review. Hum Reprod. 2017;32(5):1033–45.
Letrozol
e

39. Outline
 Introduction
 PCOS
 Unexplained infertility
 Fertility preservation for breast cancer
 Frozen embryo transfer
 Decreases OHSS

40. Endometrial preparation protocols in FET
 FET is becoming more and more popular.
 Natural cycle (NC)
 HRT
 ovarian induction

41. Values
 to promote the endometrial thickness required for embryo
implantation
 it has no anti-oestrogenic effects on the endometrium and cervical
mucus

42. Many RCTs

43. Meta-analysis : 2020

44. Outline
 Introduction
 PCOS
 Unexplained infertility
 Fertility preservation for breast cancer
 Frozen embryo transfer
 Decreases OHSS

45. Letrozole was more effective than aspirin in decreasing the incidence of
moderate and severe early-onset ovarian hyperstimulation syndrome.

46. meta-analysis including 8 studies was conducted. There were no
significantly differences in the incidence of mild, moderate, and severe
OHSS between study group with Letrozole and control group. Letrozole
has no beneficial effect on the prevention of moderate, and severe
OHSS, individually
Zhao, J., Xu, B., Huang, X. et al. Whether Letrozole could reduce the incidence of early ovary hyperstimulation syndrome after assisted
reproductive technology? A systematic review and meta-analysis. Reprod Health 17, 181 (2020). https://doi.org/10.1186/s12978-020-01042-2

47. Clinical Case

48. Day 2 of cycle
RIGHT OVARY
AFC: 18 Follicles <10mm.
TVS
LEFT OVARY
AFC: 14 Follicles <10mm.

49. 0 6 9 14
FSH ui/day
Step up protocol
8 9
75 75
C
7mm
150
10 11
112.5? 112.5
12 13
C
8mm
234
14 15
C
11mm
495
Days
Gn
E2
<10
12
14
16
18
75 75 75 75 75
1 2 3 4 … 7
End Lineal Lineal
C
6mm
75

50. 0 6 9 14
FSH ui/day
Step down regimen
Days
Gn
E2
<10
12
14
16
18
112.5
1 2 3 4 5 6
End Lineal Lineal
IVF? CANCELLATION?
hCG? COASTING?
196
7 8
75?
B-C
7mm
11 12
A
13mm
920
490
37.5?
9 10
B
10mm

51. hCG
 Dose ?
 When ?
 GnRHa?

52. Thank you
Dr. Hesham Al-Inany MD, PhD
e-mail : kaainih@yahoo.com
Mobile : 01112220298