LETROZOLE IN THE MANAGEMENT OF INFERTILITY

DR G A RAMA RAJU
Letrozole In Infertility

Contents
HISTORY LEGALITY IDEAL OVULATION
INDUCTION DRUG
MECHANISM OF ACTION
DIFFERENCE BETWEEN CC
AND LETROZOLE
GROUND BREAKING
ARTICLE
TREATMENT OPTIONS FOR
INFERTILITY
GUIDELINES
DIFFERENT TYPES OF
INFERTILITY SUMMARY

Estimates of infertility vary widely among Indian states from
Prevalence of primary infertility in India is between 3.9 & 16.8 affecting about
12 million couples!
5 in Andhra
Pradesh
3.7 per cent in
Uttar Pradesh,
Himachal Pradesh
and Maharashtra
15 in
Kashmir

DICOVERY & ROLE OF AROMATASE INHIBITORS
Angela-brodie
If you have something you think
is a good idea, stick to it,”

Robert Casper pioneering work on letrozole and ovulation

Letrozole banned in 2011
TERTOGENCITY
2005

Ideal
Ovulation
Induction
Drug

Ideal Ovulation Induction Drug
Oral administration Minimal monitoring of the cycle
No hostile effect on the
endometrium and cervical
mucus
Better ovulation rate and
pregnancy rate
Less risk of OHSS and multiple
pregnancy
Requena A, Herrero J, Landeras J, Navarro E, Neyro J, Salvador C et al. Use of letrozole in assisted reproduction: a
systematic review and meta-analysis. Human Reproduction Update. 2008;14(6):571-582.

Aromatase Inhibitor
• Inhibit or inactivate Aromatase
• Aromatase
–Cytochrome P-450 superfamily
–CYP19 gene
–Rate limiting step in estrogen production, that
is, conversion of androgens (androstenedione
and testosterone) into estrogens (estrone and
estradiol, respectively).

Classification of aromatase inhibitors
SECOND
GENERATION
3 rd.
GENERATION
LETROZOLE

MECHANISM OF ACTION (CLOMIPHENE CITRATE AND
LETROZOLE)

Mechanism of Action of Clomiphene Citrate

Mechanism of action of Letrozole

Difference between CC and letrozole

Clarification article
In this double-blind, multicentre trial, authors randomly assigned 750 women, in a 1:1 ratio, to
receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and
pregnancy, followed by tracking of pregnancies
N Engl J Med 2014;371:119-29

Outcomes with Regard to Live Birth, Ovulation, Pregnancy,
Pregnancy Loss, and Fecundity.
N Engl J Med 2014;371:119-29

Kaplan–Meier Curves for Live Birth.
N Engl J Med 2014;371:119-29

Adverse Drug Events
As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women
with the polycystic ovary syndrome
N Engl J Med 2014;371:119-29

Letrozole
Oral administration
Unifollicular development
Short half life
No depletion of ER
No antiestrogenic effect on cervical mucus and endometrial thickness
Its activity is demonstrated in the ovaries, adipose tissue brain, osteoblasts and breast

Letrozole use
Letrozole used in the following
situations
OI in polycystic ovary
syndrome (PCOS)
OI in intrauterine insemination
(IUI)
Ovarian stimulation for
IVF/ICSI

Letrozole use
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

Therapeutic use of aromatase inhibitor
Breast cancer
(hormone receptor
positive)
Induction of
ovulation (Mitwally
and Casper,2001)
Endometrial
carcinoma &
endometrial stromal
sarcoma
Endometriosis
(Sasson and Taylor
,2009).
Induction of abortion
in combination with
misopristol (Lee et al
2011).
possible role
management of
OHSS

Dose regimen of Letrozole
2.5 mg /day from
cycle day 3 to 7
(Mitwally and
Casper,2001)
5 mg/day from
cycle day 3 to 7 (Al-
Fadhli et al ,2006).
20 mg once on
cycle day 3
(Mitwally and
Casper,2005).
2.5 mg/day from
cycle day 1 to 10
(Badawy et al,2009

Contraindications of letrozole therapy
Hypersensitivity to Letrozole Pregnancy
Lactation
Severe renal impairment
(Requena et al , 2008).

Side effects of Letrozole therapy
Hot flashes (11%), Nausea (7%) Fatigue (5%)
Alopecia and vaginal bleeding
Complications occur more
frequently in breast cancer
patients than in women treated
for ovulation induction due to
differences in the duration of
treatment (Requena et al , 2008).

AACE and ESC Recommendations
• Clomiphene citrate (or comparable estrogen modulators such
as Letrozole) as the first-line treatment of anovulatory
infertility in women with PCOS.
Endocrine Society Clinical
Guideline (2013)
• Treatment for women with PCOS and anovulatory infertility
should begin with an oral agent such as clomiphene citrate or
Letrozole, an aromatase inhibitor.
American Association of Clinical
Endocrinologists, American College
of Endocrinology, And Androgen
Excess & PCOS Society (2015)

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

ROLE OF AROMATASE INHIBITORS (LETROZOLE) IN DIFFERENT
TYPES OF INFERTILITY

Anovulatory women with PCOS
A pooled analysis of four early randomized
trials has shown a significantly higher
pregnancy rate in women treated with
letrozole or anastrozole compared with
CC.
On the other hand , a large randomized
trial failed to detect any significant
difference in the pregnancy rate between
both management options (Badawy et al..
2007).

Unexplained infertility
Five trials compared aromatase inhibitors versus CC and four trials compared aromatase
inhibitors plus gonadotropins versus CC plus gonadotrophins.
Pregnancy rate was comparable between both management options (Polyzos et al .2009).

Clomiphene citrate resistant PCOS
LETRIZOLE GONADROPHINS

Aromatase inhibitors VERSUS Laparoscopy ovarian drilling
CC resistance
NOW SOLUTION
LETROZOLE
OVARIAN DRILLING IS
OBSOLETE AND NO ROLE
a decade ago only
gonadotrophins

Aromatase inhibitors for IUI
Letrozole
Day 3-7
FSH 100
Day 8
Till follicle
reaches
18 mm

ROLE IN IVF
MILD STIMULATION
POOR RESPONDER

Aromatase inhibitors for IVF
In theory, the low estradiol
level in letrozole / FSH
regimen could result in a
favourable endometrium,
and a high implantation
rate.
Furthermore , there should
be lower incidence of
ovarian hyperstimulation
syndrome and premature
luteinization.
Moreover, aromatase
inhibitors increases the
sensitivity of the growing
follicles to FSH stimulation.

Role of
Letrozole in
management
of ohss
Ohss evolving concepts

REDUCES OHSS
Pigment
epithelium-derived
factor (PEDF)
lower vascular
epithelial growth
factor (VEGF),

YOUNG AGE-CANCER .IVF
Endocrine
breast ovarian
Uterus

Use of letrozole for fertility preservation in oncological patients
Supraphysiologic oestradiol
levels resultant of the
ovulation induction with
gonadotropins may promote
the growth of estrogen
sensitive tumours (breast and
endometrial cancer).
The use of aromatase
inhibitors in combination with
gonadotropins for
superovulation to freeze
embryos in patients with
oestrogen sensitive tumours.
The main advantage of this
regimen is that the peak
estradiol levels are closer to
estradiol levels observed in
natural cycles.

Summary
Better pregnancy
outcomes and higher
live births compared to
CC in PCOS patients
Effective even in
patients with CC-
resistant PCOS
Reduces Gonadotrophin
dose and superior
alternative to CC in
combined
Gonadotrophin cycles
Monofollicular
development and lower
multiple pregnancies
No anti-estrogenic
effects on endometrium
& cervical mucus
Lower cycle cancellation
and risk of
hyperstimulation is
negligible
Safety established in
clinical studies

GOOD ARTICLE ON UNDERSTADING LETRIZOLE EVOLUTION

Video lecture of the talk.
• lecture

LETROZOLE IN THE MANAGEMENT OF INFERTILITY

LETROZOLE IN THE MANAGEMENT OF INFERTILITY

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