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)- 2016-17 Managing Committee Member: BOGS- 2016-17 East 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 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

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

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

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

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

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%)

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

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

Letrozole as Ovulation Inducer

Causes of Subfertility 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 ↑/ Normal Normal, high LH Hypothalamo-Pituitary Dysfucntion (Predominantly PCOS) >90 Type III ↑ Ovarian Failure 10

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

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

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

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: 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. 23

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.

Concept study: Letrozole for OI 25

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

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

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 -7.

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

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

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

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

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

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.

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.

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

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

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

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: 760-771; Harriet et al. Drugs 1998; 56(6):1125-1140; Bhatnagar AS. Breast Cancer Res Treat 2007;105:7–17 40

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 24-36 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

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: 760-771.

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

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