LetrozoleLetrozole: : Let’s role with it in infertilityLet’s role with it in infertility

Shannon DeGroteShannon DeGrotePharmD 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 infertility Determine the role of letrozole in infertility

treatmenttreatment

ObjectivesObjectives

• Failure to achieve a clinical pregnancy after Failure 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%-PCOSEugonadotropic:70-85%-PCOS

Hypogonadotropic5-10%-Low body weight

Hypogonadotropic5-10%-Low body weight

Aggressive Tx-FSH-IUI-IVF

Aggressive Tx-FSH-IUI-IVF

FSH<20FSH<20

Egg donationAdoptionChildfree Living

Egg donationAdoptionChildfree Living

FSH>20or<40yo& amenorrhea

FSH>20or<40yo& amenorrhea

CC 50mg x 5dCC 50mg x 5d

ResponseResponse No responseNo response

Continue 3-4 cyclesContinue 3-4 cycles

Increase dose100->150->200Increase dose100->150->200

Not pregnantNot pregnant No responseNo response

CC-IUIX 3-4CC-IUIX 3-4

FSH-IUIX 3-4FSH-IUIX 3-4

LaparoscopyLaparoscopy

IVFIVF

BleedingBleeding No bleedingNo bleeding

Menotropins±IUIx4 cyclesMenotropins±IUIx4 cycles

ProveraProvera

Adapted from: Women’s Health: a primary care clinical guide. 2004; 3rd Ed.:227-60

• Inhibition of estrogenic negative feedback loop in Inhibition 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 induced Given 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

3.3. 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 InhibitorsAndrostenedioneAndrostenedione

EstroneEstrone

TestosteroneTestosterone

EstradiolEstradiol

AromataseAromatase

1st Gen aminoglutethimide

2nd Gen

Type 1

formestane

Type 2

fadrozole

3rd Gen

Type 1

exemestane

Type 2

anastrozole, letrozole

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

LetrozoleLetrozoleIndication 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 following Outcome of 150 babies following treatment with letrozole treatment with letrozole

Group # Avg. AgeTotal

Malformation

Cardiac Malformation

Bone Malformation

Normal deliveries

36,050

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 among Congenital 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 progesteroneFertil. Steril. 2006;85:1761-5

*P=0.02

Congenital malformations among Congenital malformations among 911 newborns911 newborns

Common malformations:•Ventricular septal defect (VSD)•Polydactyly•Preauricular skin tag•Cleft palate•Down syndrome

Perc

enta

ge

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

Mature

follicle #

Endometrial 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

Sohrabvand 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 DrugFSH dose (IU)

Estradiol

(pmol/l) on hCG day

Pregnancy rate %

Healey 2003

L 5mg+FSH 600*Not

stated21.6

FSH 940*Not

stated20.9

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 DrugFSH dose (IU)

Estradiol

(pmol/l) on hCG day

Implantation rate %

Pregnancy rate %

Goswami 2004

L 2.5mg+FSH

150* 227* Not stated 23

FSH2865*

380* Not stated 24

Garcia-Velasco 2005

L 2.5mg+FSH

3627 770 25* 22.4

FSH 3804 813 9.4* 15.2School-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?