This document contains information from Dr. Shashwat Jani regarding ovarian stimulation protocols for IUI. It discusses various stimulation options including clomiphene citrate, letrozole, gonadotropins, and combinations. It provides details on dosing, monitoring, and the advantages and disadvantages of different protocols. The goal of stimulation is to develop multiple follicles to improve pregnancy rates with IUI or develop a single follicle for anovulatory patients.

1. Dr. Shashwat Jani.
M. S. ( Obs – Gyn )
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. 1.Improvement of Follicular Growth
2.Increasing the Number of Follicles
3.Treatment of Anovulation (PCOS)
4.Better Timing
5.Improvement of Luteal Phase
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Dr Shashwat Jani.
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3. Optimum Ovarian Stimulation
for IUI
 2 – 3 follicles with 18 – 19 mm size.
 Endometrium  9 mm thick & trilaminar.
 IUI between Cycle D13 and D16, 36-40
hrs. from HCG inj.
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Dr Shashwat Jani.
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4.  Provides more number of follicles with good
quality.
 Timing of HCG injection predicts ovulation
better, so as to schedule IUI near ovulation time.
 C.O.H. offers more over for fertilization &
implantation, hence increases success.
 C.O.H. corrects subtle endocrinopathies which
block ovulation, implantation
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Dr Shashwat Jani.
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5.  Retrograde Ejaculation
 Impotence or Ejaculatory Dysfunction
 Hypospadias
 Hypospermia (Low Volume)
 Non Liquefying / highly viscous semen
 ‘Subnormal’ semen parameters
 Seminal Antisperm Antibody
 Unexplained Infertility.
Dr Shashwat Jani.
9909944160 524-Apr-17

6.  Vaginismus
 Cervical Hostility
 Ovulatory Dysfunction
 Mild Endometriosis
 Allergy to seminal plasma
 Unexplained infertility
Dr Shashwat Jani.
9909944160 624-Apr-17

7.  Azoospermia with testicular failure
 Severely abnormal semen parameters Use
Discretion)
 Hereditary disease in man
 Severe untreatable Rh isoimmunisation in
wife
 Repeated failures with IVF/ICSI
 Single women, lesbian couples
Dr Shashwat Jani.
9909944160 724-Apr-17

8. Simple
Cost Effective
Minimal side effects
Best success rates
Patients requiring ovarian
stimulation or induction can be
categorized in two groups :
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Dr Shashwat Jani.
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9.  In these patients there is an established
ovulatory pattern.
 Multiple studies have shown improved
pregnancy rates with ovarian stimulation
in these patients as compared to
nonstimulated natural cycles.
 Aim : Multiple follicle development
Dr Shashwat Jani.
9909944160 924-Apr-17

10.  20 – 30 % cases of female infertility
 Anovulatory patients are further divided
by WHO into 3 categories:
Group I: Hypogonadotrophic
hypogonadism
Group II: PCOS
Group III: Ovarian failure
 Aim : Monofollicular development
Dr Shashwat Jani.
9909944160 1024-Apr-17

11. Natural
cycle + IUI
3.3%
CC + IUI
9.5%
CC + hmG
+ IUI
13.3%
hmG + IUI
17.26%
Stimulation Protocol
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Dr Shashwat Jani.
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12. Number of
follicles
Pregnancies
per cycle
(%)
ONE
5.7%
TWO
13.6%
THREE
16.3%
FOUR OR
MORE
13.9%
Number Of Follicles
Higher pregnancy rate with three preovulatory
follicles (Huttenen et al 1999)
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Dr Shashwat Jani.
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13. D 2 FSH
( >10 mlU/ml is s/o low ovarian reserve )
AFC
Ovarian Volume
AMH
HSG / Lap
Dr Shashwat Jani.
9909944160 1324-Apr-17

14. 1. Clomiphene citrate (CC)
2. Letrozole
3. Gonadotropins
4. Clomiphene with Gonadotrophins
5. Letrozole with gonadotrophins
6. Gonadotrophins with GnRH analogues
7. Gonadotrophins with GnRH antagonists
Dr Shashwat Jani.
9909944160 1424-Apr-17

15.  The cumulative pregnancy rate per couple
was 33% for IUI & COH, & 18% for IUI alone.
 COH has independent positive effect on
pregnancy rate when combined with IUI.
 In young patients without a prior pelvic surgery
& with good-post-wash semen quality COH
doubles IUI pregnancy rate.
Hendin B, Falcone T, Hallak J, Nelson D, Vemullapalli S, Goldberg J, et al. Effect of clinical &
semen charachteristics on efficacy of ovulatory stimulation in patients undergoing
IUI. J Assist Reprod Genet 200;17:189-93.24-Apr-17 15
Dr Shashwat Jani.
9909944160

16.  Most widely used
 Simple to use,
 Minimal side effects,
 Cost effective
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Dr Shashwat Jani.
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17. 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
17
Clomiphene citrate: Mechanism of action
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

18.  50-100mg per day for five days .
(up to 200mg per day)
 There is no difference in pregnancy
rate whether clomiphene is commenced on
day 2, 3, 4 or 5 of the cycle, although there is
perhaps a tendency to multiple follicular
development the closer the agent is
commenced to menses.
24-Apr-17
Dr Shashwat Jani.
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19. Pregnancy: 30%
Failure (no pregnancy despite
ovulation): 40%
Resistance: no ovulation: 25%
Antiestrogenic effect: 5%
Dr Shashwat Jani.
9909944160 1924-Apr-17

20.  Shows excellent result in ….
 CC Resistant
 CC Failure .
 Associated with thicker endometrium and
increased stromal blood flow, thereby providing
a better uterine environment more favorable for
implantation.
 Compared to CC, letrozole has been shown
to have higher pregnancy rates.
Dr Shashwat Jani.
9909944160 2024-Apr-17

21. • 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
21
Letrozole: Mechanism of action
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.

22.  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 monofolliculer
 No direct antiestrogenic adverse effect on
endometrium
 Shorter half-life (48hr and 2 wks)
 Lower serum E2
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Dr Shashwat Jani.
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23.  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.
9909944160 2324-Apr-17

24.  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
Dr Shashwat Jani.
9909944160 2424-Apr-17

25.  Indicated in :
- CC Failure
- Letrozole failure
- WHO Group 1 (Hypogonadotrophic hypogonadism )
 Cochrane ( 2007 ) …
“ Gonadotropins might be the most effective drugs
when IUI is combined with ovarian hyperstimulation .”
Dr Shashwat Jani.
9909944160 2524-Apr-17

26.  FSH or hMG administered daily from early in
the Menstrual Cycle.
 Monitoring with USG ( and Hormonal assays )
is mandatory
 Trigger ovulation with hCG when follicular
maturity attained
 Significantly improve pregnancy rates from
IUI, in contrast to natural cycle IUI.
 Risk of multiple pregnancy
Dr Shashwat Jani.
9909944160 2624-Apr-17

27. Advantages:
 high efficacy:
ovulation rate : >95 % per cycle
conception rate: 20 - 30 % per ovulatory cycle
Limitations:
 Serious complications can occur:
multiple pregnancies
▪ Twins 25%
▪ Higher order 5 %
ovarian hyperstimulation syndrome
long term complication ? ovarian cancer
 require intensive monitoring in specialist centre
 expensive
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Dr Shashwat Jani.
9909944160 27

28.  Depends on the D2 LH / FSH /E2 levels.
 If LH FSH containing gonadotrophins are
indicated,
 Whereas if serum FSH (>10 mIU/ml),
LH + FSH is used for ovarian stimulation.
 For ovarian stimulation in patients with
hypogonadotrophic hypogonadism, a
combination of LH and FSH is used.
Dr Shashwat Jani.
9909944160 2824-Apr-17

29. A. Conventional regimen
B. Low dose step up regime
C. Step down regime
Dr Shashwat Jani.
9909944160 2924-Apr-17

30. Days 7 14 21 28
hCG
150 IU 112.5 IU 75 IU hCG
Foll.  10 mm
75-150 U daily
6 12
hCG
Foll.  16mm
37.5 IU 75 IU 112.5 IU 150 IU
Chronic Low dose Step up regimen
Step down
Conventional Regime
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Dr Shashwat Jani.
9909944160 30

31. CC resistant OR CC Failure Cases
Started from D2 / D3
75 - 150 IU /day
Serial USG for monitoring
D 8 S. estradiol
Widely accepted protocol .
PR up to 30 %
Dr Shashwat Jani.
9909944160 3124-Apr-17

32.  Useful in PCOS
 AIM :
To find the “threshold“ level of FSH
which will lead to the development of a single
preovulatory follicle.
 Less complication
 But , unphysiological as FSH is very high in late
follicular phase compared to natural cycle.
Dr Shashwat Jani.
9909944160 3224-Apr-17

33.  Low starting dose (37.5- 75 units/day )
 Stepwise increase in subsequent doses
 E2 & USG on D7
 D8 E2 > 200 pg/ml OR follicle > 10mm
Ct. Same dose.
 If E2 or Follicle size not achieved on D8
increase dose by 37.5 IU /day .
Dr Shashwat Jani.
9909944160 3324-Apr-17

34.  HMG / FSH 150 IU/day from D2
 Continued till Dominant follicle become 10mm
on USG
 Decrease the dose .
 112.5 IU/day for next 3 days
 75 IU day till time of HCG.
Dr Shashwat Jani.
9909944160 3424-Apr-17

35.  Sequential use of CC f / b FSH or HMG.
 CC ( 100 mg ) 1 daily from D2 to D6.
 FSH or HMG ( 75 / 150 IU ) on D6 & D8.
 TVS on D8 onwards
 Additional FSH / HMG given.
Dr Shashwat Jani.
9909944160 3524-Apr-17

36.  Higher pregnancy rate than with CC alone .
 More cost effective, as the dosage of
gonadotrophins is reduced .
 Lesser multiple pregnancy rate than with
gonadotrophins alone .
 Lower incidence of OHSS, as compared to the
conventional regime.
 Kemmann E, Jones J R. Sequential clomiphene Citrate menotrophin therapy for
induction or enhancement of ovulation.Fertil Steril 1983;39:772-9
 Dickey R P, Olar T T, Taylor S N, Curole D N, Rye P H . Sequential clomiphene citrate and
Human menopausal Gonadotrophin for ovulation induction: comparison to clomiphene
citrate alone and human menopausal gonadotrophin alone.. Human Reprod 1993; 8:56-
59Dr Shashwat Jani.
9909944160 3624-Apr-17

37.  Good alternative to CC in patients with
unexplained infertility undergoing
gonadotrophin stimulated COH cycles
combined with IUI therapy.
 In a prospective nonrandomized study by
Mitwally and Casper it was shown that
aromatase inhibition with letrozole reduced
the dosage of FSH required for COH without
any undesirable antiestrogenic effects,
Dr Shashwat Jani.
9909944160 3724-Apr-17

38.  The pregnancy rate achieved was
also significantly lower in the
CC + FSH group (10.5%) compared
with the letrozole + FSH group (19.1%)
and FSH only group (18.7%).
Dr Shashwat Jani.
9909944160 3824-Apr-17

39.  In almost 15-20 % of cycles of CC or HMG
 Due to multi follicular development,
Estradiol Increases
Premature LH surge
Cycle Cancellation.
Dr Shashwat Jani.
9909944160 3924-Apr-17

40.  To avoid this endogenous LH interference,
Exogenous Gonadotrophins & GnRH
analogues are used for OI.
 Mainly useful in IVF.
 Recent Cochrane review has concluded that
GnRH analogues do not significantly
improve pregnancy rates in IUI.
Dr Shashwat Jani.
9909944160 4024-Apr-17

41.  Act by competitive inhibition of
GnRH receptors, which results in
rapid decline in FSH /LH levels, thus
preventing premature LH surge.
 Can be given in a single dose or daily
dose regimen.
Dr Shashwat Jani.
9909944160 4124-Apr-17

42. 1. Lubeck Protocol:
Gonadotrophins are started as usual
and antagonist is started when the follicle
reaches a size of 14 mm, or from 6 day of
stimulation onwards in a dose of 0.25mg / day
till the day of HCG injection.
Dr Shashwat Jani.
9909944160 42
Diedrich K , Diedrich C , Santos E , Zoll C , Al-Hasani S , Reissmann T , et al. Suppression of the
endogenous luteinizing hormone surge by the gonadotrophin-releasing hormone antagonist
Cetrorelix during ovarian stimulation . Hum Reprod. 1994; 9:788-791.
24-Apr-17

43. 2. French Protocol :
Gonadotrophins are started as usual
and a single dose (3 mg) of antagonist is
given when serum E2 level is about 150-200
pg/ml and follicular size is 14 mm .
Dr Shashwat Jani.
9909944160 43
Olivennes F , Fanchin R , Bouchard P , de Ziegler D , Taieb J , Selva J , et al. . The single or dual
administration of the gonadotropin-releasing hormone antagonist Cetrorelix in an in vitro
fertilizationembryo transfer program. Fertil Steril. 1994;62:468
24-Apr-17

44. 1. Allows the manipulation of follicular
development so that IUI can be avoided at
weekends without any detrimental effect on PR.
2. Compared to agonist , it is relatively simple
and inexpensive. There is no suppression of
oestrogen and the effects are easily reversible.
3. Antagonists are associated with lower
rates of OHSS.
Dr Shashwat Jani.
9909944160 4424-Apr-17

45. Dr Shashwat Jani.
9909944160 4524-Apr-17

46.  D2 TVS
 Serial TVS from D8  to look for follicular
development ( Number & Size ).
 Normally follicle grow 2 – 3 mm/day
 helps in determining exact time to trigger
ovulation
 Prevent OHSS
 Endometrium: look for thickness &
appearance.
 Triple line ET of > 9 – 10 mm is ideal .
Dr Shashwat Jani.
9909944160 4624-Apr-17

47.  In Natural Cycle : Serum E2 level correlates
with development of dominant follicle.
 In Stimulated cycle: it reflects the total
output of all developing follicle irrespective of
size.
 Problem : Inconvenience , Cost , daily Prick
 Mainly used in Gonadotrophin cycle on D8 ,
Value > 200 pg/ml  Good response.
Dr Shashwat Jani.
9909944160 4724-Apr-17

48.  > 4 follicles of > 16 mm OR > 8 follicles of > 12 mm
 Serum Estradiol
 > 1500 – 2000 pg / ml
Cancel the cycle
 If < 1500 pg/ ml  use GnRH analogue to trigger
ovulation
Dr Shashwat Jani.
9909944160 4824-Apr-17

49.  Premature LH surge is known to occur in
20 to 24% of patients undergoing ovarian
stimulation after the leading follicle reaches
16 mm.
 The LH surge can be detected either by
doing a daily blood or urinary LH assay, once
the leading follicle exceeds 16 mm.
 When LH surge detected  Inj. HCG given &
IUI planned.
Dr Shashwat Jani.
9909944160 4924-Apr-17

50.  Ideally 36 -38 after HCG administration
OR
After Confirmation of Ovulation.
50
Dr Shashwat Jani.
990994416024-Apr-17

51.  The HCG injection is necessary as the LH
secreted by the body may not be adequate
enough, to induce the necessary maturational
changes in all oocytes, if there are many
follicles in the ovary.
 Numerous urinary LH kits are available to
detect LH surge. They are easy to use and are
cost effective.
Dr Shashwat Jani.
9909944160 5124-Apr-17

52. 24-Apr-17 52
Dr Shashwat Jani. +91
9909944160