Letrozole in Ovulation Induction

Induz 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

Iris Hospital, Kolkata

Behala Balananda Brahmachary Hospital, Kolkata

Secretary, Perinatology Committee: Bengal Obstetric and Gynaecological Society (BOGS)- 2016-17

Managing Committee Member: BOGS- 2016-17

15 Publications: National and International Journals

NOTICE

Medicine is an ever-changing science. As new research and clinical

experience broaden our knowledge, changes in treatment and drug

therapy are required. The authors and the publisher of this work have

checked with sources believed to be reliable in their efforts to provide

information that is complete and generally in accord with the standards

accepted at the time of publication. However, in view of the possibility of

human error or changes in medical sciences, neither the authors nor the

publisher nor any other party who has been involved in the preparation or

publication of this work warrants that the information contained herein is in

every respect accurate or complete, and they disclaim all responsibility for

any errors or omissions or for the results obtained from use of the information

contained in this work. Readers are encouraged to confirm the information

contained herein with other sources.

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

Number of newborns with major malformations

Percent of newborns with malformations

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

N= 3928

LTZ stimulation reduces risk of miscarriage, with no increase in risk of major

congenital anomalies or adverse pregnancy

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

Structural malformations &

chromosomal abnormalities

N= 623

Natural conception group

5 / 171 babies

(2.9%)

LTZ group5 / 201 babies

(2.5%)

CC group10 / 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.

15th Jan 2017

Ban On Letrozole Lifted After 5 Long Years By DCGI

13

Letrozole Revoked

MINISTRY OF HEALTH AND FAMILY WELFARE [(Department of Health and

Family Welfare) NOTIFICATION: New Delhi, the 17th February, 2017 G.S.R. 145(E)]

Current Clinical Guidelines

For women with PCOS and BMI >30, letrozole should be

considered as first-line therapy for ovulation induction

because of the increased live birth rate compared with

clomiphene citrate

Endocrine Society Clinical Guideline (2013) recommends:

Clomiphene citrate (or comparable estrogen modulators such as

Letrozole) as the first-line treatment of anovulatory infertility in women

with PCOS.

American Association of Clinical Endocrinologists, American College of

Endocrinology, And Androgen Excess & PCOS Society (2015)

Treatment for women with PCOS and anovulatory infertility should

begin with an oral agent such as clomiphene citrate or Letrozole, an

aromatase inhibitor.

CC should be first-line pharmacotherapy for ovulation induction and letrozole can also be

used as first-line therapy.

Letrozole as

Ovulation

Inducer

Clomiphene Citrate

Ovulation: 70-80% cases

Pregnancy rate: 10-20%/cycle*

not more then 6 cycle continuously and not more then 12 cycles in life time

..to avoid possible Risk of (?) Ovarian Malignancy (NICE, 2013)

In doses of 50 mg/d /cycle and can be increased to 150 mg until ovulation is achieved

*Pavone ME, et al. J Clin Endocrinol Metab. 2013 May; 98(5): 1838–1844.

CC Resistance/ Failure

CC RESISTANT:

If patient fails to ovulate despite 3 CC cycles

About 20-25% of Anovulatory women are CC- resistant*

CC FAILURE:

CC-resistant

women who ovulate, but do not get pregnant

Women who get pregnant but end in miscarriage

*Mitwally MF, et al. Fertil Steril. 2001 Feb;75(2):305-9, Azargoon A, et al. Iran J Reprod Med. 2012 Jan; 10(1): 33–40.

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

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.

granulosa cells

FSH

aromatase

LH

theca cells

androstenedioneestrogen

Follicular Physiology

Aromatase

1. Ovary

2. Adipose tissue

3. Brain

Exogenous FSH

CC binds to ER & depletes

receptor concentrations

aromatase inhibitors

Follicular Development

Pituitary gland

FSH

Stimulates follicular growth Estrogen

Large follicles (more FSH receptors) Smaller follicles (less FSH receptors)

Continues to grow (mono follicular) Atresia

Ovulation

Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013

Follicular Development

Pituitary gland

FSH

Stimulates follicular growth Estrogen

Large follicles (more FSH receptors) Smaller follicles (less FSH receptors)

Continues to grow (mono follicular) Atresia

Ovulation

CC → No feedback inhibition

Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013

Follicular Development

Pituitary gland

FSH

Stimulates follicular growth Estrogen

Large follicles (more FSH receptors) Smaller follicles (less FSH receptors)

Continues to grow (mono follicular) Atresia

Ovulation

CC → No feedback inhibition

Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013

Follicular Development

Pituitary gland

FSH

Stimulates follicular growth Estrogen

Follicles with FSH receptors Smaller follicles (less FSH receptors)

Continues to grow (multi follicular) Atresia

Ovulation

CC → No feedback inhibition

Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013

Follicular Development

Pituitary gland

FSH

Stimulates follicular growth Estrogen

Large follicles (more FSH receptors) Smaller follicles (less FSH receptors)

Continues to grow (mono follicular) Atresia

Ovulation

Letrozole → maintains feedback

inhibition

Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013

Follicular Development

Pituitary gland

FSH

Stimulates follicular growth Estrogen

Large follicles (more FSH receptors) Smaller follicles (less FSH receptors)

Continues to grow (mono follicular) Atresia

Ovulation

Letrozole → maintains feedback

inhibition

Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013

Letrozole vs CC

Letrozole vs CC

Letrozole (Aromatase Inhibitor)

Blocks Aromatase Does not block ER

Increased intraovarian androgen 1. No adverse effect on endometrium/

cervix

Augment FSH receptors Stimulates IGF-I 2. No hot flush

Synergistically promotes follicular growth

Clomiphene (Anti-estrogen)

Blocks ER

1. ↓ endometrial thickness↓glandular density↓ uterine blood flow in luteal

phase

2. ↓quantity/ quality of Cx mucus

3. Hot flushes (prolonged accumulation in tissues→ prolonged depletion of ER)

J Clin Endocrinol Metab, March 2006, 91(3):760 –771 J Hum Reprod Sci 2011 May-Aug; 4(2): 76–79. J Hum Reprod Sci 2013 Apr-Jun; 6(2): 93–98

Letrozole vs CC

Letrozole (Aromatase Inhibitor)

Blocks Aromatase Does not block ER

Increased intraovarian androgen 1. No adverse effect on endometrium/

cervix

Augment FSH receptors Stimulates IGF-I 2. No hot flush

Synergistically promotes follicular growth

Clomiphene (Anti-estrogen)

Blocks ER

1. ↓ endometrial thickness↓glandular density↓ uterine blood flow in luteal

phase

2. ↓quantity/ quality of Cx mucus

3. Hot flushes (prolonged accumulation in tissues→ prolonged depletion of ER)

J Clin Endocrinol Metab, March 2006, 91(3):760 –771 J Hum Reprod Sci 2011 May-Aug; 4(2): 76–79. J Hum Reprod Sci 2013 Apr-Jun; 6(2): 93–98

Letrozole vs CC

Letrozole (Aromatase Inhibitor)

Blocks Aromatase Does not block ER

Increased intraovarian androgen 1. No adverse effect on endometrium/

cervix

Augment FSH receptors Stimulates IGF-I 2. No hot flush

Synergistically promotes follicular growth

Clomiphene (Anti-estrogen)

Blocks ER

1. ↓ endometrial thickness↓glandular density↓ uterine blood flow in luteal

phase

2. ↓quantity/ quality of Cx mucus

3. Hot flushes (prolonged accumulation in tissues→ prolonged depletion of ER)

J Clin Endocrinol Metab, March 2006, 91(3):760 –771 J Hum Reprod Sci 2011 May-Aug; 4(2): 76–79. J Hum Reprod Sci 2013 Apr-Jun; 6(2): 93–98

Clomiphene citrate vs Letrozole

Letrozole Uses

Letrozole has been used in the following three

situations:

OI in polycystic ovary syndrome (PCOS)

OI in intrauterine insemination (IUI)

Ovarian stimulation for IVF/ICSI

Letrozole for OI in polycystic ovary

syndrome (PCOS)

Clinical Evidence

CONCLUSION: letrozole showed a better endometrial response and pregnancy rate

compared to CC

Endometrial thickness on the day of hCG

administration (mm) 9.1±0.3 6.3±1.1 0.014 (S)

Roy KK, et al. J Hum Reprod Sci. 2012 Jan-Apr; 5(1): 20–25.

Population Studied

7 studies out of 232 selected

• N= 1833 patients

– LTZ: 906

– CC: 927

• N= 4999 ovulation cycles

– LTZ: 2455

– CC: 2544

OUTCOME MEASURES

Primary outcome measure:

Live birth rate (LBR)

Secondary outcomes measures:

Ovulation rate per cycle

Clinical pregnancy rate

Miscarriage rate

Multiple pregnancy rates

Result

statistically significant increase in the live birth and pregnancy rates in the letrozole group when

compared to the CC group

Conclusion

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

CC 100 mg for at least 6 cycles → failure to form the DF, then put on letrozole ; 5 mg for 5 days for 4 cycles →

unable to form the DF, combination therapy (letrozole 5 mg + CC100 mg) for 5 days

PCOS patients resistant to clomiphene and letrozole used alone as single agents, Letrozole with CC

combination may be used as a first-line therapy to induce ovulation in severe cases of PCOS in order

to save time and expense

Statistically significantly increased the ovulation rate by 33.3% in the treatment group

letrozole can be used as an effective and simple alternate ovulation-inducing agent in these

women

Fertility and Sterility Vol. 94, No. 7, December 2010

N=94 : letrozole ( 2.5 mg/day) + HMG,

N= 90: CC (50 mg/day) + HMG,

N=71: HMG only.

All women received one treatment regimen in one treatment cycle.

All patients were given HMG 75 IU on alternate days daily starting on day 3 or day 7 until the day of

administration of hCG.

hCG 10,000 IU : when at least 1 follicle with mean diameter ≥18 mm

Pts advised natural intercourse after 24-36 hours after hCG

Results Ovulation rate and Clinical Pregnancy Rates

Other parameters

Conclusion

Letrozole in combination

with hMG

reduced duration of

stimulation and total HMG

dose needed for stimulation

significantly higher

monofollicular

development

The regimen of letrozole + HMG is more effective and safer than CC + HMG or HMG

alone for ovulation induction in cases of CC resistance

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.

60 moderately obese patients with PCOS

N=31 clomiphene citrate-metformin

N=29 letrozole-metformin therapy.

Stimulation was carried out for the procedures of intrauterine insemination (IUI).

60 moderately obese patients with PCOS

N=31 clomiphene citrate-metformin

N=29 letrozole-metformin therapy.

Stimulation was carried out for the procedures of intrauterine insemination (IUI).

RESULTS:

0

2

4

6

8

10

letrozole+metformin CC+metformin

8.9

6.3

En

do

metr

ial T

hic

kn

ess

(m

m)

0

5

10

15

20

25

Letrozole+metformin CC+Metformin

20.6

9.6

Pre

gn

an

cy R

ate

aft

er

thir

d I

UI

cycl

e (

%)

Fig : Showing Endometrial Thickness Fig : Preg Rate after third IUI cycle

Conclusion: Study demonstrated the advantages of the use of letrozole over clomiphene citrate in

combination with metformin in moderately obese patients with PCOS who are resistant to

stimulation with clomiphene citrate alone.

Letrozole for OI in intrauterine

insemination (IUI)

Clinical Evidence

Methods

group A :Letrozole (5 mg) for five days and gonadotrophins (HMG) 75 IU once daily for 3−5 days

group B : Clomiphene Citrate (50 mg) for 5 days and gonadotrophins (HMG) in a dose of 75 IU for 3–5days

Results

Patients co-treated with Letrozole required fewer gonadotrophins administrations and had a thicker endometrium

The pregnancy rate was not significantly different between two groups (11% vs. 12.6%)

J Reprod Infertil 2013 Jul-Sep; 14(3): 138–142.

Conclusion:

The addition of Letrozole to gonadotrophins decreases gonadotrophins requirements and improves

endometrial thickness, without a significant effect on pregnancy rates

180 infertile women:

Group A: 5 mg/day letrozole on day 3-7 of menstrual cycle.

Group B: 100 mg/day clomiphene in the same way as letrozole.

hMG administered in both groups every day starting on day between 6-8 of

cycle.

hCG(5000 IU) trigger when have two follicles of ≥16 mm.

IUI was performed 36 hr later.

Int J Reprod Biomed (Yazd).2017 Jan;15(1):49-54.

Results

0

5

10

Letrozole+ HMGCC+HMG

3.83.7

8.998.46

En

do

metr

ial T

hic

kn

ess

(m

m)

Fig 2: Showing Endometrial Thickness

Before treatment

After Treatment

0

2

4

6

Letrozole+ HMG CC+HMG

5.7

Ovari

an

Hyp

ers

tim

ula

tio

n (

%)

Fig 3: Showing Ovarian

Hyperstimulation

0

10

20

30

Letrozole+ HMG

CC+HMG

26.51

12.64

Cli

nic

al P

reg

nan

cy R

ate

(%

)

Fig 1: Showing Clinical Pregnancy Rate

Letrozole for OI in In Vitro

Fertilization (IVF)

Clinical Evidence

RCTs regarding use of letrozole for ovulation induction in

IVF/ICSI cycles

Journal of Human Reproductive Sciences / Volume 6 / Issue 2 / Apr - Jun 2013

Letrozole in IVF

Normal ovarian response

Addition of letrozole showed higher implantation and ongoing pregnancy rates

and significantly improved endometrial thickness

Poor responders

Lower dose of gonadotropin required in the letrozole cotreatment group in all

trials

Summary

Better pregnancy outcomes & higher live births compared to

CC in PCOS patients

Effective even in patients with CC-resistant PCOS

Reduces Gonadotrophin dose & superior alternative to CC in

combined Gonadotrophin cycles

Monofollicular development & lower multiple pregnancies

No anti-estrogenic effects on endometrium & cervical mucus

Lower cycle cancellation & risk of hyperstimulation is

negligible

Safety established in clinical studies