Letrozole in Ovulation Induction

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Dr Sujoy DasguptaMBBS (Gold Medalist, Hons)

MS (Obst & Gynae- Gold Medalist)DNB, FIAOG

Fellow- reproductive Endocrinology and Infertility (ACOG, USA)

Assistant Professor: SRIMSH, Durgapur

Consultant: RSV Hospital, KolkataBehala Balananda Brahmachary Hospital, KolkataTechno India Hospital, Kolkata

Secretary, Perinatology Committee: Bengal Obstetric and Gynaecological Society (BOGS)- 2016-17Managing Committee Member: BOGS- 2016-17East Zone Representative, FOGSI Youth Cell (FOGSI Future) 2017-18

15 Publications: National and International Journals

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Incidence of all malformations was not different betweenthe 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

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Fertil Steril. 2006 Jun;85(6):1761-5

No difference in overall rates of major & minor congenital malformationsamong 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 isunfounded based on this data

Number of newborns with major malformations

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Percent of newborns with malformations

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

LTZ stimulation

Reduces risk of miscarriage

No increase in risk of

Major congenital anomalies

Adverse pregnancy outcomes

Adverse neonatal outcomes

Conclusions

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Safer option for mild ovarian stimulation

Sharma S, et al. PLoS ONE. 2014; 9(10): e108219

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Structural malformations &

chromosomal abnormalities

Natural conception group

5 / 171 babies

(2.9%)

LTZ group5 / 201 babies

(2.5%)

CC group10 / 251 babies

(3.9%)

Other StudiesReference 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

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

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Letrozole as Ovulation

Inducer

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Causes of Subfertility

Ovulatory

20%

Male Factor

30%Tubal

25%

Unexplained

25%

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NICE Guidelines. Fertility Problems: Assessment and Treatment

nice.org.uk/guidance/cg156

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

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granulosa cells

FSH

aromatase

LH

theca cells

androstenedioneestrogen

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Follicular Physiology

Aromatase

Exogenous FSH

CC binds to ER & depletes

receptor concentrations

aromatase inhibition

Management of PCOS-Anovulation

Life Style Modification

CC

1st Line Treatment

No Ovulation (CC Resistance)

Metformin + CC FSH Lap Ovarian Drilling Letrozole

Ovulates

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Management of PCOS-Anovulation

Life Style Modification

CC

1st Line Treatment

No Ovulation (CC Resistance)

Metformin + CC FSH Lap Ovarian Drilling Letrozole

Ovulates

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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

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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.

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.

Concept study: Letrozole for OI

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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

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Concept study: Conclusions

Mitwally MF, et al. Fertil Steril. 2001 Feb;75(2):305-9.

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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 OI28

-7.

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

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

Primary outcome: LBR

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

Secondary outcome: Pregnancy

rate

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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

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

Conclusion

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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.

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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.

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Letrozole plus Gn in CC-resistant

infertile women with PCOS

Xi W, et al. Drug Des Devel Ther. 2015; 9: 6001–6008.

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Conclusion

LTZ in combination with

HMG

Reduce risks of OHSS in CC-resistant women with PCOS

More appropriate in patients sensitive to gonadotropin

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GuidelinesSociety 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

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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

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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

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

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Dose >2.5 mg/ d andmore than 3 cycles is not recommended

TVS Monitoring

TVS Monitoring is recommended at least in 1st cycle

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

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Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

Summary

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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