Update on LETROZOLE Current Guidelines for Ovulation Induction LET NOT FORGET WHY ?? LETROZOLE was withdrawn from Indian market (2012) “SAFETY ISSUES” “Could Be Teratogenic In Human”?

1. Update on LETROZOLE
Current Guidelines
for Ovulation Induction
DR. SHARDA JAIN

2. Over 300 ppts are available on
slideshare.net ***for use of public/Doctors
www.slideshare.net / Lifecarecentre

3. LET NOT FORGET
WHY
??
LETROZOLE was withdrawn from
Indian market (2012)
“SAFETY ISSUES”
“Could Be Teratogenic In Human”?

4. Meta-analysis cleared
all CONCERNS on malformations
BASED ON CURRENT DATA
4
Tulandi T, et al. 2006
 N=911
 No difference in overall rates of major & minor congenital malformations among newborns from
mothers who conceived after LTZ or CC treatments. Congenital cardiac anomaly is less frequent in the
LTZ group
Tatsumi T, et al. 2017 (Latest)
 N=3928
 LTZ stimulation reduces risk of miscarriage, with no increase in risk of major congenital anomalies or
adverse pregnancy or neonatal outcomes compared with natural cycles in women undergoing ART
Sharma S, et al. 2014 (Indian)
 N=623
 No significant difference in the overall rate of congenital malformations
among children born to mothers who conceived naturally or after LTZ or
CC treatment

5. 5
2017

6. How many of you missed
Letrazole in last 5 years
and why ???
This is to
inform you all
that LTZ was
not withdrawn
Globally…

7. UPDATE ON LETROZOLE
CURRENT KNOWLEDGE
CURRENT Global GUIDELINES
(2009-2017)

8. CURRENT
GUIDELINES

9. YEAR RECOMMENDATION
2016 LTZ should be considered as 1st line
therapy for OI in patients with
PCOS & BMI > 30
because of increased LBR compared to
CC
American Collage of Obstetrician
& Gynaecologists 2016

10. YEAR RECOMMENDATION
2016
CC or LTZ (when available &
permissible ) should be 1st line
pharmacological therapy to
improve fertility outcome in women
with PCOS & an ovulatory infertility
, with no other infertility factors
WHO GUIDELINE

11. Year Recommendation
2015 LTZ, under caution , could be offered as
pharmacological treatment for OI indicated for
infertility anovulatory women with PCOS with no
other infertility factors
Considered as 1st line pharmacological treatment
for OI in therapy naïve, infertility anovulatory
women with PCOS with no other infertility factors
Australian National
Health & medical research council
(NHMRC) guideline

12. YEAR RECOMMENDATION
2015 Treatment for women with PCOS & Anovulatory
infertility should begin with oral agent such as CC or
LTZ
AACE /ACE/ Androgen excess &
PCOS
Society disease state clinical review

13. Endocrine society
2013
2013 CC Or LTZ both are 1st line treatment of
Anovulatory infertility in women with PCOS

14. Role of aromatase inhibitors ?
Should they be used as First
line drug for O.I. as suggested
by almost all guidelines

15. Snap CLOMIPHENE UPDATE
in 2017
Clomiphene can be administered in
doses of 50 mg /cycle and can be
increased to 250 mg until ovulation is
achieved .Normally we do not cross
dose of 150 mg
*******
75% pregnancies occur at doses of 50-100mg
and in first 3 cycle.

16. Contra –indication and side effects of
CLOMIPHENE
• Side effects - formation of cysts,
CONTRAINDICATED in
• liver disease,
• can cause visual problems (2%),
• mood swings, headache (1%),
• depression,
• dryness and loss of hair (0.3%)
*************
• in doses more than 150 mg has less pregnancy rates.
• Less pregnancy rate is reported in PCOD

17. CLOMIPHENE – As per
RCOG Guidelines
not more then 6 cycle
continuously and not
more then 12 cycles in
life time ..to avoid possible Risk
of Ovarian Malignancy

18. CLOMIPHENE CYCLES
N = 5268
Ovulation - 3858 (73%)
Pregnancy rate - 1909 (36%)
miscarriage - 20%
Multiple Pregnancy rate - 8%
Homburg. Hum reprod . 2005

19. SHOULD WE MONITOR CLOMIPHENE CYCLE
WITH ULTRASOUND & give HCG as trigger ??
With U/S + hCG No U/S or hCG
n 105 150
Cumulative
Pregnancy rate
48% 34.7%
Deliveries 35.6% 26.7%
Multiple
Pregnancies
0 1
Konig, homburg et al, ESHRE, 2009

20. AROMATASE INHIBITORS
SHOULD THEY BE USED as first line Drug
Aromatase inhibitors are a serious
challenge to replace clomiphene as the
first line of treatment for WHO group II
Anovulatory women.
These are non- steroidal compounds that suppress
estrogen biosynthesis by blocking the action of the
the enzyme aromatase which convert
androstenedione and testosterone to estrogens

21. 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
SINGLE FOLLICLE DEVELOPMENT IN NATURAL CYCLES
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

22. Duration of FSH secretion
increased by exogenous FSH
injections
Smaller follicles stimulated to
grow by continued FSH
support
Multiple follicles develop to
mature state
Increased risk of
hyperstimulation & multiple
pregnancies
Exogenous FSH
Estrogen feedback does not
work with exogenous FSH
More smaller follicles
are rescued
Multiple follicle develop
stimulation continues
 Risk of hyperstimulation
& multiple pregnancies
22
MULTIPLE FOLLICLE DEVELOPMENT IN ART CYCLES
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

23. 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
LETROZOLE: MECHANISM OF ACTION
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

24. Clomiphene
citrate
Letrozole
Mono-follicular vs.
multi-follicular development24

25. MONOFOLLICULAR DEVELOPMENT
IS THE KEY
Though initially estrogen production is impaired with
aromatase inhibitors eventually with rise of FSH ,
estrogen production also increases with development
of follicles as a result of which a negative feedback is
activated on the hypothalamus which will modulate
an overzealous discharge of FSH which in turn is likely
to result in monomolecular ovulation with moderate
estrogen concentrations.
This is all the more likely since letrozole has a much
shorter half life (2days) than CC.

26.  Induces ovulation
CC
pituitary/hypothala
mus
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%
CLOMIPHENE CITRATE:
ANTI-ESTROGENIC EFFECTS
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

27. AROMATESE INHIBITORS – LATROZOLE
THEORETICAL ADVANTAGES
Do Not Block estrogen receptors-
* No detrimental effect on endometrium or
cervical mucus
**Negative feedback mechanism not turned off
- less chance of multiple follicular
development.*

28. AROMATES INHIBITOR TREATMENT
Negative effect is NOT turned off..
same on day 5 & 10

29. LETROZOLE
Letrozole is the most widely
used aromatase inhibitor
It is used orally in a dose of
2.5-5mg per day(3-7 days)
and is free of any side effects.

30. ANTI – ESTROGEN EFFECT ON
ENDOMETRIUM of CC
• Endometrial thinning in 15-50%
(gonen & casper , 1990 ; dickey et al, 1993)
• no pregnancies when endometrial thickness
at mid-cycle < 7 mm
• Not dose related & recurs in repeat cycles

31.  CC RESISTANT:
 If patient fails to ovulate despite 3 CC cycles
 CC failure: CC-resistant plus women who ovulate, but
do not get pregnant or get pregnant but end in
miscarriage
 About 20-25% of Anovulatory women are CC-
resistant*
CLOMIPHENE
RESISTANTANCE / FAILURE
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.

32. Management of CC-resistant PCOS
Obese women
Lifestyle modifications
=weight loss (Diet + Exercise):
If BMI> 29 kg/m2
Non-obese women
*Metformin + CC (3-6 cycles)
**Letrozole (3-6 cycles)
LOD
Gonadotropins
In vitro fertilization
Failure
Hashim HA (2012). Management of Women with Clomifene Citrate Resistant Polycystic Ovary Syndrome – An Evidence Based Approach,
Polycystic Ovary Syndrome, Dr. Mukherjee S. (Ed.), InTech. LOD: Laparoscopic ovarian drilling.

33.  Rapid clearance of drug from body
 Reversible aromatase inhibition
 Elevated FSH supports more
aromatase synthesis
Will limit androgen accumulation
in ovaries
Estrogen production should be
relatively normal at time of
ovulation
androstenedione  estrogen
aromatase
Will it affect oocyte and
pregnancy results?
 androstenedione
increased follicular
sensitivity to FSH
Testosterone
augments FSH
receptors in follicle
Testosterone
augments IGF in
follicle
 folliculogenesis
WOULD LOW ESTROGEN/HIGH ANDROGEN
LEVELS BE HARMFUL?
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

34. CASPER AND MITWALLY (2003)
• Letrozole seems to be giving promising results as
shown by comparison of a very large number of
cycles for timed intercourse or IUI .
• 3groups included Natural ( 423),
• CC(994) and letrozole – (167)treated cycles
• The pregnancy rate with letrozole was more than
thrice than in natural or CC-stimulated cycles ;
• multiple pregnancy and abortion was significantly
lower in LTZ cycles compared with CC cycles.

35. Bayer et al.
They compared CC with letrozole as the first line of
drug for ovulation induction in polycystic ovarian
disease, they found that though ovulation occurred
in 64.7% as compared to 74.5% in CC group (not
statistically significant difference ),pregnancy was
achieved in 9.1% of the cycles in letrozole group and
7.4% in the CC group (no statistical significance ),
they concluded that letrozole is an acceptable
alternative to CC as an ovulation induction agent in
PCOD.

36. ROLE OF AROMATASE INHIBITORS
in studies..prior to 2009
• Advantage over LTZ as the first line
drug for ovulation induction to replace
CC as the first line of drug for ovulation
induction….was not clear cut…except
in CASPER study ..it was felt probably
some more strong evidence is required,
• however LTZ is an attractive
alternative to CC.

37. Another concern USING
AROMATASE INHIBITORS
There are concerns raised as to the
theoretical possibity of accumulation of
androgens in a women with PCOS,
however there are no reports which
indicate towards manifestation or
worsening of clinical and biochemical
hyperandrogenism following
use of letrozole in PCOS

38. CONCERN OF INCREASED ANDROGENS
USING AROMATASE INHIBITORS..
In fact these increased androgens may
have a stimulatory & beneficiary effect
in early follicular FSH receptors
expression and therefore amplifying FSH
response this may explain the relative
increased success of combined letrozole
ands FSH for ovulation stimulation in
improving the response to FSH in
IUI/ART cycles

39. 39
Recent Clinical Evidence
2009-2017
STUDIES

40. CC V/S LETROZOLE
Parameters Clomiphene citrate Letrozole
MOA SERM Aromatase inhibitor
*Half-life Long, 5-7 days Short, 45 h
Anti-estrogenic
effects
Thin endometrium &
altered cervical mucus
Thick endometrium &
favourable cervical
mucus
Uterine blood flow Decreased Increased
*Miscarriages Possibly high Less incidence
*OHSS risk High Low
*Multiple
pregnancy
High Low

41. LETROZOLE VS CLOMIFENE
LARGO ET AL, ASRM 2013
• N= 750 PCOS , RCT
LETROZOLE CC P
OVULATION 61.4% 48.3% 0.001
PREG LOSS 31.8% 28.2% ns
TWINS 3.2% 7.4% ns
LIVE BIRTHS 27.5% 19.5% 0.007

42. 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*
42

43. STUDY DESIGN
750 US women, 18-40
yrs, BMI~35, PCOS
since 3-4 yrs
Spontaneous/
withdrawal bleeding:
MPA 5 mg/d X 10 d
RCT
1:1
CC
50 mg/d started on
Day 3 X 5 days
(N=376)
 For up to 5
cycles
 Dose increased
in subsequent
cycles in non-
responders up
to maximum:
 CC: 50 mg TID;
 LTZ: 2.5 TID
Drop-out:
73 (19.5%)
Drop-out:
85 (22.6%)
LTZ
2.5 mg/d started on
Day 3 X 5 days
(N=374)
Efficacy
variables:
Primary: Live
birth
Secondary:
Ovulation,
singleton
pregnancy,
pregnancy
loss,
congenital
anomalies
Legro RS, et al. N Engl J Med. 2014 Jul 10;371(2):119-29.
Double-blind
Multicenter
PCOS: polycystic ovary syndrome
MPA: medroxyprogesterone acetate;
CC: clomiphene citrate
LTZ: letrozole
43
Inclusion: no other causes of infertility,
no thyroid disease, hyperPRL, no
confounding medications, normal
semen of male partner

44. Letrozole versus Clomiphene for
Infertility
in PCOS: Results
Legro RS, et al. N Engl J Med. 2014 Jul 10;371(2):119-29.
19.1%
27.5%
45
44%

45. SECONDARY OUTCOMES
 Rate of pregnancy loss, pregnancy duration, birth weight
(BW)& rates of neonatal complications (including anomalies)
were comparable between groups
 Twin pregnancy rate lower with LTZ than with CC (not
significant)
 Overall birth-defect rate was similar
 Major congenital anomalies: LTZ 4; CC 1 (Not significant)
Legro RS, et al. N Engl J Med. 2014 Jul 10;371(2):119-29.

46. 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.
47

47. 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 rate
Banerjee Ray P, et al. Arch Gynecol Obstet. 2012 Mar;285(3):873-7.
Exclusion:
• Who taken confounding
medicines in past 2 mths
• Other causes of infertility
• Systemic diseases
Natural
intercourse
*Repeated cycles

48. 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

49. CONCLUSION
LTZ has beneficial effect on endometrium, thereby potentially
increasing pregnancy rates after successful OI in women with
PCOS
Banerjee Ray P, et al. Arch Gynecol Obstet. 2012 Mar;285(3):873-7.

50. 52
Another Indian study…..

51. 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
RCTSpontaneous
/ 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

52. 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
55
*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

53. SAFETY
 OHSS
 LTZ grp: None
 CC group: 2 mild cases
 Multiple pregnancies
 LTZ grp: None
 CC group: 2 Twin & 1 triplet pregnancies
 Spontaneous abortion
 Similar in both groups (4.08% in LTZ group vs. 7.42% in CC group)
[p=0.132 ]
Roy KK, et al. J Hum Reprod Sci. 2012 Jan-Apr; 5(1): 20–25.
56

54. CONCLUSION
…safe & better alternative to CC in OI protocol
for patients of Anovulatory PCOS
…may be considered as 1st line treatment for OI
Letrozole
Roy KK, et al. J Hum Reprod Sci. 2012 Jan-Apr; 5(1): 20–25.
57

55. Rogue M, et al. 2015
• N=1833
• LTZ is superior to CC when considering the live
birth & pregnancy rates in patients with PCOS

56. 59
META-ANALYSIS

57. Roque M, et al. Gynecol Endocrinol. 2015;31(12):917-21
STUDY DESIGN
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

58. LTZ is superior to CC considering
live birth & pregnancy rates in
patients with PCOS
CONCLUSION
Roque M, et al. Gynecol Endocrinol. 2015;31(12):917-21
61

59. 62
IN CC-RESISTANT PCOS

60. 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.
64

61. Letrozole plus Gn in CC-resistant
infertile women with PCOS:
Study design
LTZ+GT/CC+GT/GT

62. Letrozole plus Gn in CC-resistant infertile
women with PCOS: Study design
255 Chinese
women, <35 yrs
& BMI-26-28,
CC-resistant
PCOS for 2 yrs
Non-
randomised
LTZ 2.5 mg/d
D 3-7 of cycle +
HMG 75 IU on alternate days
from D 7 up to 10 days (D 17)*
(N=94 patients)
hCG 10 000 IU :
when at least 1
follicle with a mean
diameter ≥18 mm
HMG 75 IU on alternate days
from D 3 up to 14 days (D 17)*
(N=71 patients)
Spontaneous/
withdrawal
bleeding
CC 50 mg/d
D 3-7 of cycle +
HMG 75 IU on alternate days
from D 7 up to 10 days (D 17)*
(N=90 patients)
*HMG 75 IU was administered up to D 17 or until follicle diameter ≥18 mmXi W, et al. Drug Des Devel Ther. 2015; 9: 6001–6008.
HMG: Human menopausal gonadotropin; Single cycle
67
CC-resistant - failed to ovulate after CC 100
mg/d X 5 days for at least 3 cycles,
No other causes of infertility,
No systemic disease
No previous Gn therapy
Natural
intercourse 24-
36 hrs after hCG
End points: Ovulation
rate, monofollicular
cycles, cycle cancellation,
dose & duration of HMG,
pregnancy& multiple
pregnancy rate

63. 86.2%
80.2%80.0%
68.3%
74.6%
54.7%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
Ovulation rate Monofollicular development
LTZ + HMG CC + HMG HMG alone
NS
RESULTS: OVULATION RATE &
CLINICAL PREGNANCY RATE
*
NS: not significant; *p< 0.05; Le + HMG vs both groups
Xi W, et al. Drug Des Devel Ther. 2015; 9: 6001–6008.
68
24.7%
23.6%
22.6%
21.5%
22.0%
22.5%
23.0%
23.5%
24.0%
24.5%
25.0%
LTZ + HMG CC + HMG HMG onlyClinicalpregnancyrate
NS
NS: not significant, P >0.05

64. RESULTS: OTHER PARAMETERS
Xi W, et al. Drug Des Devel Ther. 2015; 9: 6001–6008.

65. Results: Other parameters
Xi W, et al. Drug Des Devel Ther. 2015; 9: 6001–6008.
70

66. Conclusion
LTZ in combination
with HMG
Reduce risks of OHSS in CC-
resistant women with PCOS
More appropriate in patients
sensitive to gonadotropin
Xi W, et al. Drug Des Devel Ther. 2015; 9: 6001–6008.
71

67. TAKE HOME KEY MASSEGES
OF STUDIES 2009----2017
Better pregnancy outcomes &
higher live
births compared to CC in PCOS
patients

68. Effective even in patients
with CC-resistant PCOS
TAKE HOME KEY MASSEGES
OF STUDIES 2012----2017

69. Reduces Gonadotrophin dose &
superior alternative to
CC in combined Gonadotrophin
cycles
TAKE HOME KEY MASSEGES
OF STUDIES 2012----2017

70. Monofollicular
development & lower
multiple pregnancies
TAKE HOME KEY MASSEGES
OF STUDIES 2012----2017

71. No anti-estrogenic effects on
endometrium & cervical
mucus
TAKE HOME KEY MASSEGES
OF STUDIES 2012----2017

72. Lower cycle cancellation & risk
of hyperstimulation is
negligible
TAKE HOME KEY MASSEGES
OF STUDIES 2012----2017

73. Safety established in clinical
studies
TAKE HOME KEY MASSEGES
OF STUDIES 2012----2017

74. ADDRESS
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