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Ovulation induction in IUI
PERFORMANCE
Dr.Shiuli Mukherjee
MBBS,MD,FNB(Reproductive Medicine)
Infertility & IVF consultant
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• 35 years old lady suffering from primary infertility,
husband normozoospermic, HSG-B/L spillage
positive, AMH- 1.5, had 6 cycles of ovulation
induction with clomiphene citrate and timed coitus
(unmonitored cycle), not conceived. Now planned for
IUI (AIH). How to stimulate?
•
•
•
•
CC + Gonadotrophin
Anestrazole
Continuous Gonadotrophin
Continuous Gn + antagonist
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Learning Objectives
At the conclusion of the presentation participants
should be able to answer:
• Why we need ovulation
induction?
• How to stimulate ovary?
• How to monitor?
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Controlled ovarian stimulation in IUI cycle
OBJECTIVE:
To produce more than one egg for better
chance of pregnancy
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Different drugs and stimulation
protocols used for IUI
3 TYPES OF DRUGs
6 TYPES OF PROTOCOLS
• Clomiphene citrate
• 3 CONVENTIONAL
• Letrozole/anestrazole
• 3 NON CONVENTIONAL
• GONADOTROPIN –
FSH or HMG
• GnRH AGONIST or
ANTAGONIST
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Why different drugs and protocols?
• All patients are not equal responders to a particular
type of stimulation
• Response basically depends on :
• OVARIAN RESERVE - 3 A
Age
AFC (Antral follicle count)
AMH (Anti Mullerian Hormone)
• PELVIC PATHOLOGY
• BMI
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AFC and AMH
• AFC – follicles between
5-10 mm diameter on
day 2 – 3
• AMH secreted by early
antral follicles
• Both predict ovarian
response accurately.
Jayaprakasan K, et al. Fertil. Steril. 93(3), (2010),
La Marca A,et al. Hum. Reprod. Update 16(2), 113–130 (2010).
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Different protocols of stimulation
CONVENTIONAL:
• Cc with or without adjuncts
• Cc with ‘soft’ gonadotropin stimulation
– Scattered d3, d5, d7, d9 with cc
– Sequential after completion of cc d5 or d7 
– Fixed d3 & d8 with cc
• Continuous low dose gonadotropin stimulation
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Our publication….
Mukherjee Shiuli, Sharma Sunita, Chakravarty BN, JHRS, 3;2 ,2010
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And result……
• Significant
improvement in
pregnancy rate in CC +
gonadotrophin group
particularly in
anovulatory patients.
• Miscarriage rate
remain same.
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Protocols …. contd
NON CONVENTIONAL:
• Low dose GnRHa followed by soft protocol CC +
FSH/HMG stimulation –
Amenorrhoeric PCOS
Recent case study on Mrs.N.Saha with very high LH and resistant PCOS
• Cc / HMG  antagonist
– When lead follicle is 14mm
– In the morning of day of hCG
• Recent recFSH / LH protocol for competent
monofollicular development
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CC with or without adjuncts
• CC– 100 mg daily from d3 – d7
• Adjuncts: eltroxin, bromocriptine, metformin,
dexamethasone as & when necessary
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Cc with soft protocol gonadotropin
(d3/d8)
Cheap – as well as effective
• Gonadotropin on d3 – why ?
to recruit one or two additional co-dominant follicles
• Gn on d8 – why ?
to counteract antioestrogenic effect of CC and to
enhance preovulatory oestradiol level for effective LH surge
Mukherjee et al, Journal of Human Repro Sci, 2010
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Continuous low dose gonadotropin
OBJECTIVES:
• To compensate low levels of FSH compared to LH in early
follicular phase as in PCOS
• To recruit additional codominant follicles in early follicular
phase
• Antioestrogenic effect of CC is avoided
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LOW DOSE GnRH-A FOLLOWED BY SOFT PROTOCOL CC-FSH
AMENORRHOEIC PCOS
WITHDRAWAL
OC PILL D5 - D25
LUPRIDE 0.5-1 ML SC DAILY D16 – D25 or D21 till bleeding
WITHDRAWAL
CC (100mg) D3 – D7
+
GN (75 IUI) 1 amp. INJ. D3 , D5 & D7
IUI
Also applicable in non amenorrhoic PCOS (to down regulate LH)
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Soft protocol stimulation with CC /HMG +
antagonist
PROTOCOL
CC (D3-D7)
+
rFSH / HMG (75IU) Daily Or On Alternate Days From D5
+
Flexible Multiple Dose Of Cetrorelix When Lead Follicular
Diameter Is 14mm – 1 Or 2 Doses
Mukherjee et al, Journal of Human Reprod Sci, 2012
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Literature review- our publication….
• Significant improvement in pregnancy rate
• No OHSS
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Soft protocol + antagonist …. contd
OBSERVATION :
• Dose of cetrorelix may have to be increased from
0.25mg to 0.5mg in order to decrease number of
LH surges
COMMENT:
• Antagonist with CC for soft protocol should be
cautiously used (Engel et al, 2002)
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Gn ANTAGONIST & IUI
• CYCLE STIMULATION WITH GONADOTROPIN (HMG) RATHER
THAN WITH CC AND ANTAGONIST FOLLOWED BY IUI –
RESULTS ARE BETTER THAN WITH GONADOTROPIN ALONE
• PREVENTS PREMATURE LH RISE AND LUTEINISATION (Allegra
et al, 2007)
• IN MONOFOLLICULAR DEVELOPMENT EARLY DECLINE OF E2
AND ONSET OF BLEEDING
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Recent protocol for monofollicular
development
Addition of hCG/rLH instead of HMG in late follicular phase
(under trial)
• rFSH(150IU) daily for 7 days
• Decrease FSH dose (50, 25, 0 IU)
• Start increasing dose of hCG (50, 100, 200 IU)
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ADVANTAGES
• Support development of larger follicles
• Expedite regression of small follicles
• Low risk of OHSS
• Hcg is less expensive than lh; longer half life, therefore
more effective
• No risk of leutinization
(Fillicori 2002)
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RECENT PROTOCOL … CONTD
CONCEPT IS BASED ON NORMAL PHYSIOLOGY OF
OVULATION
– EARLY FOLLICULAR PHASE (D1 TO D4)
• MORE FSH IS ESSENTIAL –
• SMALL AMOUNT OF LH IS AVAILABLE FROM ENDOGENOUS
SOURCE
– MID FOLLICULAR PHASE (D5, D6)
• DOMINANT FOLLICLE IS SELECTED – HAS BOTH FSH, LH
RECEPTORS
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OVULATION – PHYSIOLOGY …. CONTD
LATE FOLLICULAR PHASE (D6 TO D12)
– DOMINANT FOLLICLE IS LH DEPENDANT – PRODUCES
ENOUGH E2
– ABSENCE OF FSH AND DOMINANCE OF LH CAUSES
FOLLICULAR ATRESIA –
– MONOFOLLICULAR DEVELOPMENT
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MONITORING OF OVARIAN RESPONSE
• SERIAL FOLLICULOMETRY
• CERVICAL MUCOUS STUDY FERNING PATTERN
1ST ORDER BRANCHING
2ND ORDER BRANCHING
SERUM E2 & SERIAL URINARY LH ESTIMATION 
NOT PERFORMED NOW-A-DAYS
• ENDOMETRIAL THICKNESS
• LH Kit assessment
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2ND ORDER BRANCHING OF FERN - E2 PEAK - hCG
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TIMING OF hCG ADMINISTRATION
NOT TOO EARLY, NEITHER TOO LATE
HOW TO DETERMINE ?
• DOMINANT FOLLICLE – 17-19mm
• CERVICAL MUCOUS – 2ND ORDER BRANCHING; CLEAR
TRANSPARENT MUCOUS
E2 – 100-150 PG/FOLLICLE
• IN CASE OF 3RD ORDER BRANCHING (BREAKAGE OF
BRANCHES, DARK BACKGROUND)
LH SURGE STARTED
– NO hCG (SPONTANEOUS OVULATION)
• P4 SHOULD BE LESS THAT 1.2ng/ml
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LH Kit
• Preferably to done when
dominant follicle reaches
18mm with ET >7 mm,
isoechoic, trilayered.
• IUI ideally to be done on
the same day preferably
by evening if LH kit
become positive by
morning.
Speroff et al, 2010
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USG PREDICTION OF
FAVOURABLE/UNFAVOURABLE RESPONSE
• FOLLICLES
• NO IN COHORT
• DAILY INCREASE IN
DIAMETER
• PERIFOLLICULAR
BLOOD FLOW
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USG PREDICTION OF
FAVOURABLE/UNFAVOURABLE RESPONSE…contd.
• ENDOMETRIAL
THICKNESS, TEXTURE &
BLOOD FLOW
• > 7 mm ON HCG DAY
• ISOECHOIC WITH TRIPLE
LINE
• S.E. BLOOD FLOW
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Gonadotrophins !!!!!!!!!!
• Why use?
• When/where to use?
• What to use?
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HISTORY
1978 !!
Early 1980- CC+uGn
Late 1980- uGn
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• First extracted from pig pituitaries or pregnant horses.
• 1950, extracted from human cadaver pituitary glands
or urine of postmenopausal women.
• hMG 1964, purified hMG 1982, HP hMG 1992.
• Late 1990s-: Recombinant Gonadotrophins
– Genetically engineered Chinese hamster ovary -
Follitrophin alpha & Follitrophin beta.
• Late 1980s – GnRH agonist
• Late 2000 - GnRH antagonists
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3 GENERATIONS OF GONADOTROPHINS
• Urinary gonadotrophins (FSH & HMG)
• Purified/ Highly purified Urinary gonadotrophins [
virtually no LH & < 5% proteins ]
• Recombinant FSH ,
99% pure FSH, No LH, high consistency
• Recombinant LH
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Why ?
• Gonadotrophins are the cornerstones
of ART treatment
• More follicles, more gamets, more embryos enhancing pregnancy rate
• In specific situation like hypogonadotrophic
hypogonadism (HH) WHO group I
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Paradise lost ..
Paradise regained
• Premature LH surge
Poor quality
No fertilization or very poor pregnancy rate
Cancel egg retrieval
5-20%
All cycles treated in 1980’s
36
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Paradise regained………
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GnRH agonist-antagonist
Agonist
• LEUPROLIDE-.5 ,1 mg.
Antagonist
• CETRORELIX-.25 mg
• BUSERELIN-.2,.5 mcg
• GOSERELIN-3.6 MG
•
TRIPTORELIN-.1,.05 mg
• GANIRELIX-.25
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Action of GnRH agonists
downregulation
GnRH
LH + FSH
GnRH - receptor
post-receptor-cascade
pituitary
flare suppression
up effect
39
GnRH - agonist
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Action of GnRH antagonists
GnRH
LH + FSH
GnRH - receptor
post-receptor-cascade
pituitary suppression
40
GnRH - antagonist
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Where / When ?
• In specific situation like hypogonadotrophic
hypogonadism (HH) WHO group I
• CC resistant or CC failure - WHO group II
• POF - WHO group III
• IVF stimulation as a routine
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Proceed step by step
• Protocol selection
agonist(long,short,ultrashort) vs antagonist
• Dose calculation –ovarian reserve -3 A
AFC, Age, AMH
• Monitoring
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The long luteal protocol
ovulation
induction
gonadotropin administration
in an individualized dosage
oocyte
pick up
embryo
transfer
start of
GnRH agonist
22nd day
of previous
cycle
1st day
of gonadotropins
STOP GnRH
43
luteal phase support
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The Cetrotide® 0.25 mg
multiple dose protocol
ovulation
induction
gonadotropin administration
in an individualized dosage
oocyte
pick up
embryo
transfer
1st day
of menstruation
1st day
of gonadotropins
luteal phase support
Cetrotide® 0.25 mg administration
daily s.c. starting on day 6 of stimulation
45
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Ovulation Induction – r/u FSH
hCG 5000
Dosage
STEP DOWN
150 IU/d
100 IU/d
50 IU/d
D1
D7
D14
Days
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Dosage
hCG 5000
STEP UP
ø foll > 10 mm
150 IU /d
100 IU / d
50 IU / d
D1
D7
D14
Days
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What to use?
• Urinary ? P / HP
• Urinary / Recombinant?
• FSH vs HMG vs LH
• Agonist vs antagonist
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Advantages of Rec. FSH
•
•
•
•
•
•
•
•
•
•
Recombinant DNA technology: unlimited supply
Batch to batch consistency
 allergic reactions,  potential risk of infection
High specific activity: less acid isoforms
Sub-cutaneous administration
Increased % of mature eggs.
Enhanced embryo cleavage
Increased implantation rate
More embryos for freezing, better quality embryos
Is the use of r FSH cost effective?
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Literature review
• R-FSH – 16% increased chance of having a baby.
• 40% more U-HMG needed to have a baby
compared with r FSH.
• Cochrane review - No statistical significant
difference in live birth rate between rFSH and
HP FSH.
• Choice depend on availability, convenience and
cost
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Advantages of GnRH-antagonists
- Fits into the normal cycle - patients friendly
- Less side effects in comparison to the long
protocol:
1. Ø cysts
2. Ø hormonal withdrawl
3. Significant reduction of OHSS
4. Simple
- No significant difference in the probability
of live birth between GnRH-agonists and
antagonists
Al-Inany et al, 2012
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The future of ovarian stimulation
FSH CTP s.c.
1
2
GnRH-Antagonist p.o.
3
4
5
6
7
8
9
10
11
cycle day
12
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The future of ovarian stimulation
Oral LH Mimetic
Depot FSH s.c.
1
2
3
GnRH-Antagonist p.o.
4
5
6
7
8
9
10
11
12
cycle day
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The future of ovarian stimulation
Oral LH Mimetic
Oral FSH mimetic
1
2
3
GnRH-Antagonist p.o.
4
5
6
7
8
9
10
11
12
cycle day
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