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Uploaded byShannon DeGrote
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Letrozole Final

This document discusses the use of letrozole in infertility treatment. It begins by reviewing infertility and its typical treatments, such as intrauterine insemination and in vitro fertilization. It then discusses letrozole and aromatase inhibitors, noting that letrozole inhibits the aromatase enzyme to decrease estrogen levels. Several studies are summarized that compare the effects of letrozole to clomiphene in ovulation induction and assisted reproduction treatments. While letrozole appears to be relatively safe, the document concludes by questioning whether its theoretical advantages over clomiphene have been proven in practice.

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LetrozoleLetrozole:: Let’s role with it in infertilityLet’s role with it in infertility Shannon DeGroteShannon DeGrote PharmD Candidate 2014PharmD Candidate 2014
1.1. Review infertility and its treatmentReview infertility and its treatment 2.2. Discuss letrozole and aromatase inhibitorsDiscuss letrozole and aromatase inhibitors 3.3. Explore the safety of letrozoleExplore the safety of letrozole 4.4. Determine the role of letrozole in infertilityDetermine the role of letrozole in infertility treatmenttreatment ObjectivesObjectives
• Failure to achieve a clinical pregnancy afterFailure to achieve a clinical pregnancy after 12 months or more12 months or more • More than 10% of couples seek treatmentMore than 10% of couples seek treatment • 40% of cases are due to male infertility40% of cases are due to male infertility • Intrauterine insemination (IUI)Intrauterine insemination (IUI) • Sperm deposited closer to oocyteSperm deposited closer to oocyte • In vitro fertilization (IVF)In vitro fertilization (IVF) • Injection of sperm into oocyteInjection of sperm into oocyte Overview of infertilityOverview of infertility Goldman’s Cecil Med. 2012;24th Ed:e119-21
Hypergonadotropic: 10-30% -Ovarian failure Hypergonadotropic: 10-30% -Ovarian failure Eugonadotropic:70-85% -PCOS Eugonadotropic:70-85% -PCOS Hypogonadotropic 5-10% -Low body weight Hypogonadotropic 5-10% -Low body weight Aggressive Tx -FSH-IUI -IVF Aggressive Tx -FSH-IUI -IVF FSH<20FSH<20 Egg donation Adoption Childfree Living Egg donation Adoption Childfree Living FSH>20 or <40yo& amenorrhea FSH>20 or <40yo& amenorrhea CC 50mg x 5dCC 50mg x 5d ResponseResponse No responseNo response Continue 3-4 cycles Continue 3-4 cycles Increase dose 100->150->200 Increase dose 100->150->200 Not pregnantNot pregnant No responseNo response CC-IUI X 3-4 CC-IUI X 3-4 FSH-IUI X 3-4 FSH-IUI X 3-4 LaparoscopyLaparoscopy IVFIVF BleedingBleeding No bleeding No bleeding Menotropins±IUI x4 cycles Menotropins±IUI x4 cycles ProveraProvera Adapted from: Women’s Health: a primary care clinical guide. 2004; 3rd Ed.:227-60
• Inhibition of estrogenic negative feedback loop inInhibition of estrogenic negative feedback loop in hypothalamushypothalamus • Perceived drop of estrogen levels causing LH/FSH surgePerceived drop of estrogen levels causing LH/FSH surge 1.1. Given days 3-7 after spontaneous or inducedGiven days 3-7 after spontaneous or induced mensesmenses 2.2. Ovulatory LH surge days 12-19Ovulatory LH surge days 12-19 • Can be induced by hCG (5,000-10,000IU SQ) on day 14Can be induced by hCG (5,000-10,000IU SQ) on day 14 1.1. 75-80% ovulate but only 40-50% become pregnant75-80% ovulate but only 40-50% become pregnant • Thinning of endometriumThinning of endometrium • Production of dry, thick cervical mucusProduction of dry, thick cervical mucus ClomipheneClomiphene Goldman’s Cecil Med. 2012;24th Ed:e119-21
Aromatase InhibitorsAromatase Inhibitors AndrostenedioneAndrostenedione EstroneEstrone TestosteroneTestosterone EstradiolEstradiol AromataseAromatase 1st Gen aminoglutethimide 2nd Gen Type 1 formestane Type 2 fadrozole 3rd Gen Type 1 exemestane Type anastrozole,Holland-Frei Cancer Medicine. 2010;8th Ed.:737-49 • Inhibit CYP450 aromatase enzyme • Final step in estrogen biosynthetic pathway • Decrease levels of circulating estrogen • Two types • Type 1 • Steroidal, irreversible • Type 2 • Nonsteroidal, reversible
LetrozoleLetrozole Indication Breast cancer •Early: Adjunctive treatment with tamoxifene •Advanced • 2.5mg once daily Precautions • Cirrhosis or CrCl<10mL/min: 50% dose reduction • Decreased bone mineral density • High cholesterol ADRs Hot flashes, night sweats, nausea, arthralgia, headache, dizziness, edema T1/2 Terminal ~2 days Letrozole. In: Lexi-Comp OnlineTM
November 17th , 2005 Dear Health Care Professional: Subject: Contraindication of Femara* (letrozole) in premenopausal women “… Novartis is advising you of concerns about the use of the aromatase inhibitor Femara* (letrozole) for the purpose of ovulation induction in the treatment of infertility… There have been post-market reports of congenital anomalies in infants of mothers exposed to Femara* for the treatment of infertility.” www.novartis.ca/asknovartispharma/download.htm?res=Femara_DHCP_E_2005_Nov.pdf&resTitleId=266
Outcome of 150 babies followingOutcome of 150 babies following treatment with letrozoletreatment with letrozole Group # Avg. Age Total Malformation Cardiac Malformation Bone Malformation Normal deliveries 36,05 0 30.5 (1.2) P=0.25 95%CI= 0.78- 4.71 P=0.0006 95%CI= 3.30- 58.1 P=0.0005 95%CI=2.64- 27.0 Letrozole ± LH/FSH 150 35.2 (4.7) • Cardiac malformations may be underrepresented in control group. • St. Mary’s Community Hospital study center • Mothers were likely transferred to a tertiary care hospital for delivery for malformations diagnosed before birth Fertil. Steril. 2005;84(supp. 1):O-231
Congenital malformations amongCongenital malformations among 911 newborns911 newborns Drug # Total Malformations # Cardiac Malformations # Letrozole 514 14 1* Clomiphene 397 19 7* • Retrospective multicenter study • No significant difference in age, 32-34yo • Contributing factors • Clomiphene: 3 smoking, 1 gestational diabetes, 2 progesterone • Letrozole: 1 metformin& gestational diabetes, 1 metformin& smoking, 2 progesterone Fertil. Steril. 2006;85:1761-5 *P=0.02
Congenital malformations amongCongenital malformations among 911 newborns911 newborns Common malformations: •Ventricular septal defect (VSD) •Polydactyly •Preauricular skin tag •Cleft palate •Down syndrome Percentage Fertil. Steril. 2006;85:1761-5 2-3% total malformations in general population •0.4-1.2% cardiac
Safety clearance granted… But what about efficacy? Use of letrozole in assisted reproduction: a systematic review and meta-analysis
Study Drug Matur e follicle # Endometria l growth (mm) Ovulatory cycles % Pregnancy patient rate % Atay 2006 L 2.5mg 1.2* 8.4* 82.4* 21.6* CC 100mg 2.4* 5.2* 63.6* 9.1* Bayar 2006 L 2.5mg 1 8 65.7 21.6 CC 100mg 1 8 74.7 19.4 Sohrabva nd 2006 L 2.5mg+M 1.9 8.2* 90.6 34.5 CC 100mg+M 1.8 5.5* 80.6 16.7 Badaway 2007 L 5mg 2.3 8.1* 67.5 37.6 CC 100mg 3.1 9.2* 70.9 42.7 Aromatase inhibitors in PCOS I2 > 50% indicating studies were not statistically homogenous Hum. Reprod. Update. 2008;14:571-82 *P<0.05 M = metformin
Letrozole & FSH for IUILetrozole & FSH for IUI Study Drug FSH dose (IU) Estradiol (pmol/l) on hCG day Pregnancy rate % Healey 2003 L 5mg+FSH 600* Not stated 21.6 FSH 940* Not stated 20.9 Mitwally 2003 L+FSH 465* 1540* 22.2 FSH 1114* 3213* 21.4 Bedaiway 2007 L 2.5mg+FSH 394* 1604* 19 FSH 1317* 2585* 16 Pregnancy rate meta-analysis showed no significant difference (OR= 1.15, 95% CI 0.78-1.71) Hum. Reprod. Update. 2008;14:571-82 *P<0.05
Letrozole & FSH in IVFLetrozole & FSH in IVF Study Drug FSH dose (IU) Estradiol (pmol/l) on hCG day Implantation rate % Pregnancy rate % Goswami 2004 L 2.5mg+FSH 150* 227* Not stated 23 FSH 2865* 380* Not stated 24 Garcia- Velasco 2005 L 2.5mg+FSH 3627 770 25* 22.4 FSH 3804 813 9.4* 15.2 School- craft 2008 L+FSH 4222 1403** 15 37*# FSH 3937 3147** 21 57*# Pregnancy rate meta-analysis showed no significant difference (OR= 1.40, 95% CI 0.67-2.91) #Reported as ongoing pregnancy rate and was not included in the meta-analysis Hum. Reprod. Update. 2008;14:571-82 *P<0.05 **P<0.01
Letrozole:Letrozole: Let it go or let’s roll?Let it go or let’s roll? • Relative safety in premenopausal women • Theoretical vs actual advantage over clomiphene • Advantages in FSH-IUI and IVF • Ovarian hyperstimulation syndrome • Estrogen-dependent cancers and IVF- Frozen
Questions?Questions?