FIRST LINE THERAPY - CLOMIPHENE CITRATE & LETROZOLE BY DR SHASHWAT JANI

1. Dr. Shashwat Jani.
M. S. ( Obs – Gyn ), F.I.A.O.G.
Diploma in Advance Laparoscopy.
Consultant Assistant Professor,
Smt. N.H.L. Municipal Medical College.
Sheth V. S. General Hospital , Ahmedabad.
Mobile : +91 99099 44160.
E-mail : drshashwatjani@gmail.com

2. Introduction
“ Journey of conception begins when a mature
egg is released from ovary, pushed down the
fallopian tube and is available to be fertilized. “
• Ovulation Disruption
- Ovulation Dysfunction
- Anovulation.
• The key players of infertility.
• In the absence of successful ovulation, conception
can not be realized.
• This disrupted ovulation - Emotional
- Economical burden.
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3. 21-Apr-18
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4. Anovulation
 One of the most important causes of
female factor infertility is anovulation.
 Management of ovulatory dysfunction and
the ability to induce ovulation with the
resultant pregnancy was a big milestone in
infertility treatments.
 Commonest cause of anovulation is polycystic
ovarian disease (PCOS).
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5. Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
5
Classification of Anovulation ( WHO )
PCOS: polycystic ovarian syndrome
CC: clomiphene citrate21-Apr-18
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6.  Estrogen levels at
beginning of cycle,
removes negative
feedback on FSH
FSH levels begin to
increase to
stimulate oocytes
6
Follicle Development In Natural Cycles
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

7. FSH stimulates
granulosa cell
proliferation &
aromatase production
LH stimulates
androstenedione
production by theca
cells that diffuses into
granulosa cells
Aromatase converts
androstenedione into
estrogen
granulosa cells
FSH
aromatase
LH
theca cells
androstenedione
estrogen
7
Follicle Development :
Role Of Aromatase Enzyme
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

8. Duration of FSH secretion limited
by negative feedback from
estrogen produced by larger
follicles
Smaller follicles with fewer FSH
receptors no longer stimulated to
grow by decreasing FSH levels
undergo atresia
Therefore a single follicle reaches
maturation stage
FSH
estrogen
atresia
mature follicle
Mono follicular ovulation
Negative feedback
Reduced stimulation
8
Single Follicle Development In Natural Cycles
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

9. Supra-physiologic
synthesis of estrogen
Strong negative
feedback signals to
hypothalamus &
pituitary
Low GnRH production,
with +ve feedback on LH
Low FSH & high LH
No ovulation
Hypothalamus/Pituitary
Strong estrogen -ve feedback
Low FSH
Follicle does not develop
Low GnRH
Anovulation
Very high levels of estrogen
High LH
1
2
3
4
5
6
9
Anovulation in PCOS patients
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

10. Goals Of Ovulation Induction
 Induce Monofollicular development
 Start with least invasive and
simplest treatment option
 Maximize rate of singleton
pregnancies
 Minimize risk of OHSS
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11.  1st line treatment for OI Since many decades.
 Ovulation: 60-85% cases
 Pregnancy rate: 10-20 % / cycle
 Failure of 6 CC cycles: Other factors for infertility should
be considered
 Effective & safe oral agent but associated with many
drawbacks
11
Clomiphene Citrate
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12. Depletion of ER in
pituitary &
hypothalamus due to
prolonged stimulation
Estrogen feedback
loop gets interrupted
FSH secretion
increased leading to
multiple follicle
growth
Hypothalamus
Pituitary
CC binds to ER & depletes
receptor concentrations
More smaller follicles are rescued
Multiple follicles develop
estrogen –ve
feedback
interrupted
FSH stimulation
continues
1
2
3
4
5
12
Clomiphene citrate: Mechanism of action
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
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13. Induces ovulation
CC
Pituitary/
hypothalamus
Endometrium
Cervical mucus
isomers
Endometrial thickness < 5-6 mm
Reduction in glandular density
Decreased uterine blood flow during
early luteal phase
Change in quantity or quality of mucus
Anti-Estrogenic effects contributing to reduced pregnancy rates
Miscarriage rate of 26%
13
Clomiphene citrate: Anti-estrogenic effects
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
21-Apr-18
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14. Pharmacology
 Approximately 85% of an administered dose is
eliminated after approximately 6 days.
 As currently manufactured, CC is a mixture, in
approximately a 3:2 ratio, of 2 geometric isomers,
Enclomiphene and Zuclomiphene.
 Enclomiphene is the more potent isomer and the one
primarily responsible for the ovulation-inducing actions of
CC .
 Enclomiphene levels rise rapidly after administration
and fall to undetectable concentrations soon thereafter.
 Zuclomiphene is cleared far more slowly; levels
detectable in the circulation for more than a month after
treatment.
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15. Indications of C.C.
 Anovulation ( WHO GROUP – II )
 Oligo - ovulation
 PCOS
 LPD
 Unexplained infertility
 In certain cases of male factor infertility for
timing of ovulation
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16. Pre requisites for C.C. Therapy
 Evaluation of male partner
 History and physical examination
 Age and duration of infertility
 Cause of infertility
 Galactorrhoea and Prolactin levels.
 Thyroid function
 Pituitary function by baseline hormonal
evaluation.
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17. Recommendations For CC Usage
• Till date, CC is the most used drug for ovulation
induction and timing of ovulation.
• However, concerns about possible linkage with
later life ovarian cancer, has led the RCOG to issue
guidelines .
• The recent RCOG guidelines along with ACOG
recommendations state that CC should be used for a
maximum of 12 months in patients lifetime and for
a maximum of 6 months continuously.
• Hence, it is necessary that all cycles with CC be
carefully monitored for evidence of ovulation.
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18. Dosage Schedule & Effects
• Dose for Normal women 50-100 mg/day
• Less sensitive Upto 250 mg/day
• Extremely sensitive 25 mg/ day
• No advantage in using dose > 150 mg
• Start with 100 mg will reduce the Tt time.
 75% of pregnancies occur with in first 3 cycles
 80% will ovulate
 30-45% will get pregnant
 20-25% will not respond at all
 Can be started on Day 2/3/4/5
does not influence results
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19. Monitoring of C.C. Cycle
 Transvaginal Ultrasound
 A baseline scan on D2 or D3 & thereafter
from the D9 or D10 onwards till the follicle
shows a growth and maturation.
 Serum E2 levles
 Basal Body Temperature (BBT)
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20. Side Effects
• Multiple follicles
• Multiple pregnancies
• Thin Endometrium
• Bloating & abdominal distension
• Ovarian cyst formation ( OHSS )
• Hot flashes( DISTURBED SLEEP) 10%
• Visual disturbances 5%
• blurred vision , flashes of light
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21. CC Resistance: (Ovulation Failure)
• It is a very commonly used terminology and is
defined as “failure to ovulate with 3 months of
use at 150mg/day of 5 days”.
• The commonest cause for this is PCOS, and is
seen in about 20% of patients.
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22. CC Failures: (Conception Failure)
• There are patients who ovulate but fail to
conceive on CC therapy.
• If a patient has 3 ovulatory cycles with CC
and does not conceive then she is labeled as CC
failure and should be started on alternative
therapy. It needs to rule out CC associated
reproductive dysfunction and evaluation of
other causes of infertility.
• This may also due to antiestrogenic effect of
CC on cervical mucous and endometrium.
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23. Aromatase Inhibitors
Androstenedione
Estrone
Testosterone
Estradiol
Aromatase
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,
reversible21-Apr-18
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24. Inhibits aromatase in
ovaries & peripheral tissues
reducing estrogen levels
Negative feed back being
active stimulates
hypothalamus-pituitary axis
GnRH release produces FSH
FSH-mediated stimulation
of follicle
Rising estrogen level from
follicle
suppresses FSH leaving a
single dominant-follicle
Hypothalamus
Pituitary
-ve feedback stimulation
Smaller follicles
undergo atresia
Single follicle develop
estrogen –ve feedback
FSH stimulation
1
2
3
4
6 androstenedione  estrogen
Aromatase inhibition
GnRH released
Falling FSH
5
24
Letrozole: Mechanism of action
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25. Clomiphene
citrate
Letrozole
Mono-follicular vs.
multi-follicular development2521-Apr-18
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26. Conclusion…
Advantages of Letrozole over CC ….
1. It does not deplete ERs throughout the
body
2. It keeps the HPO axis intact
3. It is short acting (45 min halflife).
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27. That’s why…
Letrozole ensures….
improved endometrial thickness,
cervical mucus,
monofollicular, and better folliculogenesis
• Higher pregnancy rate
• Singletone pregnancy
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28. 28
Letrozole: Pharmacokinetics
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 tolerated21-Apr-18
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29. LETROZOLE
• Dose
2.5 mg/day start cycle day 3-7, max 7.5 mg/day
(AL-Fadhli et al., 2006; Legro et al., 2014 N Engl J Med)
• Comparison with CC (Casper et al., 2006)
– High rate of monofolliculr
– No direct antiestrogenic adverse effect on
endometrium
– Shorter half-life (48hr and 2 wks)
– Lower serum E2
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30. Extended Letrozole Therapy
• In a recent study conducted by Badawy et al,
extended letrozole therapy (2.5mg daily from
day-1 of menses for 10 days) was used for CC
resistant PCOS women…
 Higher number of patients ovulated
 No of dominant follicles were more
 Pregnancy rates were significantly greater
 No extra cost
Dr Shashwat Jani.
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31. Letrozole Step up Protocol
• Reported by Mitwally et al.
• In this protocol letrozole was administered in
the step up doses consisting of one, two,
three, and four tablets of letrozole (2.5mg)
daily on menstrual cycle days 2, 3, 4 and 5
respectively.
• Multifollicular development
• Higher pregnancy rate
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32. Current Uses Of Aromatase Inhibitors
In Gynecology
1. Breast Cancer
2. Endometrial Carcinoma & Endometrial
Stromal Sarcoma
3. Endometriosis
4. Induction Of Ovulation
5. Unexplained Infertility
6. Poor Responders
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33. Side Effects Of Letrozole
Letrozole is generally well tolerated …
 Headache (6.9%)
 Nausea (6.3%),
 Peripheral edema (6.2%),
 Fatigue (5.2%),
 Hot flushes (5.2%),
 Bone and back pain (4.8%),
 Hair thinning and rash (3.4%)
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34. Contraindications Of Letrozole
1. Hypersensitivity to Letrozole
2. Pregnancy
3. Lactation
4. Severe renal impairment.
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35. Concept study: Letrozole for OI
Mitwally MF, et al. Fertil Steril. 2001 Feb;75(2):305-9.
3521-Apr-18
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36. Concept study: Conclusions
Mitwally MF, et al. Fertil Steril. 2001 Feb;75(2):305-9.
3621-Apr-18
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37. 37
2012 - 2017
Recent Clinical
Evidence
In PCOS
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38. Legro RS, et al. N Engl J Med. 2014 Jul 10;371(2):119-29.
Richard S. Legro, M.D., Robert G. Brzyski, M.D., Ph.D., Michael P. Diamond, M.D., Christos Coutifaris, M.D., Ph.D., William D.
Schlaff, M.D., Peter Casson, M.D., Gregory M. Christman, M.D., Hao Huang, M.D., M.P.H., Qingshang Yan, Ph.D., Ruben Alvero,
M.D., Daniel J. Haisenleder, Ph.D., Kurt T. Barnhart, M.D., G. Wright Bates, M.D., Rebecca Usadi, M.D., Scott Lucidi, M.D.,
Valerie Baker, M.D., J.C. Trussell, M.D., Stephen A. Krawetz, Ph.D., Peter Snyder, M.D., Dana Ohl, M.D., Nanette Santoro, M.D.,
Esther Eisenberg, M.D., M.P.H., and Heping Zhang, Ph.D., for the NICHD Reproductive Medicine Network*
3821-Apr-18
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39. Conclusions
LTZ was superior to CC as a treatment for anovulatory
infertility in women with PCOS
LTZ was associated with higher live-birth &
ovulation rates
Legro RS, et al. N Engl J Med. 2014 Jul 10;371(2):119-29.
3921-Apr-18
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40. Letrozole vs. clomiphene citrate in ovulation induction
in Indian women with PCOS: Design
N= 147 PCOS
women, 18-35
yrs, BMI:28-29,
infertile since 2-
2.4 yrs
Randomised, open
label
LTZ 2.5 mg/day
from cycle D3-7
(n=69)
hCG 10000 IU: if
follicle diameter
≥18 mm
CC 100 mg/day
from cycle D3-7
(n=78)
Efficacy parameters:
 Rate of ovulation
 Average follicular
diameter on day 16
 Number of mature
follicles/cycle
 E2 level
 ET
 Pregnancy rateBanerjee Ray P, et al. Arch Gynecol Obstet. 2012 Mar;285(3):873-7.
40
Exclusion:
• Who taken confounding
medicines in past 2 mths
• Other causes of infertility
• Systemic diseases
Natural
intercourse
*Repeated cycles21-Apr-18
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41. Results
Safety: 1 patient from CC group had spontaneous abortion at 2 months gestation
Banerjee Ray P, et al. Arch Gynecol Obstet. 2012 Mar;285(3):873-7.
Parameter LTZ
(N=78, 132 cycles)
CC
(N=69, 156 cycles)
P value
Rate of ovulation 86.9% 61.5% P <0.05
Average follicular diameter on
Day 16
20.90  2.39 mm
(range 18-25 mm)
21.00  3.20 mm
(range 17-28 mm)
NS
No. of mature follicles
produced/ cycle
1.10  0.31 1.08  0.28 NS
Mean E2 level on day of hCG
administration
444.03  85.42
pg/ml
817  286.70
pg/ml
P <0.05
Mean ET 8.78  1.16 mm 8.72  1.41 mm P <0.05
Day 21 serum progesterone level 19.09  10.47
ng/ml
13.90  12 ng/ml P <0.05
Pregnancy rate 28.9% 17.9% P <0.5
E2: estradiol; ET: endometrial thickness; NS: non significant 41

42. 42
Another Indian study…..

43. Study design
OvulationMenses
1 2 3 4 5 6 7 8 9 1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
… 2
8
1 2 3 4 5 6 7 8 9 1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
… 2
8
LTZ 2.5- 5
mg/d*
hCG 10,000 IU IM
(follicle ≥18 mm/;
ET > 6 mm)
CC 50- 100
mg/d*
Timed intercourse 24-36 h
after hCG administration
Roy KK, et al. J Hum Reprod Sci. 2012 Jan-Apr; 5(1): 20–25.
Efficacy parameters:
• Mean no. of follicles
• Endometrial thickness
• Ovulatory cycle rate
• Conception rate
• Pregnancy outcome
N= 204, 20–35
yrs & BMI <28,
anovulatory
PCOS since >1
yr
RCT
43
Spontaneous
/ withdrawal
bleeding
*Treatment repeated up to 3 cycles, dose increased in
subsequent cycle if no response
37/106 in CC grp required higher dose
16/98 in LTZ grp required higher dose
Exclusion: Other causes
of infertility
Other medications: No

44. Results
Roy KK, et al. J Hum Reprod Sci. 2012 Jan-Apr; 5(1): 20–25.
Variable LTZ
(n=98, 294
cycles)
CC
(n=106, 318
cycles)
P value
No. of follicles ≥ 18 mm* 1.86  0.26 1.92  0.17 0.126
ET (mm)* 9.1  0.3 6.3  1.1 0.014
E2 (pg/mL)* 248.2  42.2 364.2  71.4 0.024
44
*on the day of hCG administration
Ovulation rate/cycle 196/294 (66.6) 216/318 (67.9) 0.712
Pregnancy rate 43 (43.8) 28 (26.4) 0.041
Live birth 39 (39.7) 21 (19.8) 0.045
Figures in parenthesis are in percentage. *on day of hCG administration

45. Letrozole vs. laparoscopic ovarian drilling in
CC - failure PCOS: Study design
Liu W, et al. Experimental and Therapeutic Medicine. 2015; 10: 1297-1302.
N=141 Chinese
women, <40 yrs,
BMI < 26, CC-
resistant* PCOS
since 3-3.3 yrs
RCT
Open label
Group A: LTZ 2.5
mg/d
from D-5 X 5 days
(N=71 patients)
hCG 8000
IU: if
follicle
diameter
18-22 mm
Group B:
Laparoscopic
ovarian drilling
(N=70 patients)
Natural
intercourse
36 hrs later
hCG: Human chorionic gonadotropin
Treatment
repeated up
to 6 cycles if
conception
failed**
Patients
followed till
6 months
45
No other cases of infertility,
systemic diseases
No medications in last 6 mnts
*CC-resistance: failure to ovulate
with 100 mg/d CC for 3 cycles
**No dose adjustment

46. Conclusions
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.
46

47. 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.
47

48. Latest evidence...2017 …!!!
Tatsumi T, et al. Hum Reprod. 2017 Jan;32(1):125-132. 48

49. “…it is the 1st study of such kind in
Asian subcontinent”
Sharma S, et al. PLoS ONE. 2014; 9(10): e108219
49

50. 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%)
Sharma S, et al. PLoS ONE. 2014; 9(10): e108219
Congenital malformations
50

51. 21-Apr-18
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52. 52
Society Year Recommendation
American College
of Obstetricians
and
Gynaecologists
2016 LTZ should be considered as 1st-line therapy for OI in patients
with PCOS & BMI > 30 because of increased LBR compared to
CC
WHO guideline 2016 CC or LTZ (when available & permissible) should be 1st line
pharmacological therapy to improve fertility outcomes in
women with PCOS & anovulatory infertility, with no other
infertility factors
Australian
National Health
and Medical
Research Council
(NHMRC)
guideline
2015 LTZ, under caution, could be offered as pharmacological
treatment for OI indicated for infertile anovulatory women
with PCOS with no other infertility factors
-Considered as 1st line pharmacological treatment for OI in
therapy naive, infertile anovulatory women with PCOS with
no other infertility factors
AACE/ACE/Androg
en Excess and
PCOS Society
Disease State
Clinical Review
2015 Treatment for women with PCOS & anovulatory infertility
should begin with oral agent such as CC or LTZ
Endocrine Society 2013 CC (or comparable estrogen modulators such as LTZ) as 1st

53. 21-Apr-18
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