Ovulation Induction Protocols for Unexplained Infertility

OVULATION INDUCTION
Protocols
UNEXPLAINED
INFERTILITY
Dr. K. Anuradha,
F.R.C.O.G.

Ovulation
Induction
• Ability to induce
ovulation and
attain
pregnancy
•One of the
greatest
achievements
Anu Test Tube Baby Centre

• Ov. Disorders –
identified in
18-25 % of
infertile women
Indications for
Ovulation Induction :-
• To stimulate ovulation in
anovulatory infertility
• To augment ovulation in
ovulatory infertility
• To stimulate production
of several mature
follicles
(cos) in conjunction
with ART

When
no specific cause –
(unexplained infertility)
‘Is OI empiric’
Anov. infertility
When a
specific cause
identified,
treatment
restores normal
cycle fecundity

Unexplained Infertility
• Basic evaluation
–Ovulation
–Adequate sperm
production and
–Patency of fallopian tubes
Additional recommendations :-
–Assessment of ovarian
reserve
–Laparoscopy &
Hysteroscopy
10 % – 30 %
of couples

Potential Difficulties - UI
• Ordering correct tests
• Performing tests
appropriately &
• Correct interpretation
• Initial diagnostic
work ups should
encompass both
partners
• A specific cause of
infertility is never
certain
 Non Diagnosis or
 Diagnostic
Ignorance ?

Unexplained Infertility
Appears to represent
–‘lower extreme of normal distribution of
fertility’ or
–A defect in fecundity, that can not be
detected
* Both diminished and
delayed fecundity

Average cycle fecundity
• Untreated control group
(in randomised and non-
randomised studies) - 1.8 – 3.8 %
• Pregnancy rates lower with-
i. Increasing age of female partner
and
ii. Duration of infertility

Increasing age of female partner
• 30 – 31 yrs.
• 37 – 38 yrs.
• 51 yrs.
 Subfertility
 Critical point
reached with approx
25,000 follicles
remaining
 Follicular count
reaches 1000
Follicles continue to decline from birth

PAO
Normal Decline 25000
Accelerated
Decline
Early
Menopause
• 37 – 38 yrs –
25,000 follicles
• 51 yrs –
menopause, 1000
follicles
Accelerated
decline in
fertility at
age
• Approx
13.5yrs
Time period
between
accelerated
decline in fertility
is fixed at
Normal Decline
25000
Accelerated
Decline
Early
Menopause

Ovarian Reserve Markers
• AMH
 3 – 5 ng/ml (normal)
 More reliable
 No cyclical variation
• AFC
 > 5 – 2-6 mm follicles
 Good predictor,
 cost effective
• FSH
 > 10 m IU / ml - low reserve
 Less reliable
 Rise when Function deeply
compromised

• Expectant observation with
T1 & Life-style changes
• Ovulation Induction with
Oral or Injectables
• IUI
• OI & IUI
• ART
Principal treatments (UI)
Therapy for UI

Ovulation induction - UI
• Is it useful
• Ovulation
inducing
agents
• When to
‘move-on’
Rationale for OI in UI
• Subtle ovulatory defects missed
by standard testing may be
overcome
• Increased no. of Oocytes
available for fertilization
may increase likelihood of
pregnancy
• IUI may increase the density of
motile sperm available to
ovulated Oocytes

Folliculogenesis
D-3 D5 D6 D8 D9 D14
Recruitement Selection Dominance
FSH -
FSH +
FSH -
Ovulation Induction
‘Gate Mehanism’ ‘Mature by chance’

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
Multiple follicle development
in ART cycles
Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771. Anu Test Tube Baby Centre

Ovulation inducing agents
oral anti-
estrogens
• CC
• Tamoxifen
Aromatase
inhibitors
• letrozole
• anastrazole
injectable
gonadotrophins
alone
With GnRH-a,
GnRH-ant.

Regimens Of Ovulation Induction
Clomiphene Citrate / Letrozole
Let./ C C + hMG
Let./C C + FSH / Rec-FSH
hMG
FSH
hMG +FSH
Rec- FSH
Rec- FSH+Others
GnRHa + hMG
GnRHantagonist + hMG

Oral antiestrogens
CC
Selective estrogen
receptor modulator
(SERM)
Tamoxifen
Mild antiestrogenic
Estrogen Agonist
Reduced negative
est. feed back
Alters GnRH sec.
pattern
Antagonist less desirable peripheral action
thinnning of endomet. & cx mucus
pituitary gonadotrophins
ovulation
20 – 40 mg/d • CC resistants
• side effects to CC

CC – Non – steroidal triphenyl ethylene
derivative (2-isomers)
En –CC (62%)
• more potent
• relatively short ½ life
Zu – clomiphene (38%)
• clears slowly
• may accumulate gradually
over a series of cycles

CC
Dosage
• orally – 25 -100 mg/d
3rd – 7th day
if responds -
ov. occurs with in 5-7 d
of last CC tab.
• extended CC regimen
7 – 10 days
side effects
• vasomotor disturbances
• visual – 1-2% reversible
• Alopecia
• Ov. enlargement
• U/s before each
new CC cycle

CC
Risks
• multiple pregnancy
• approx – 7-10%
• treat with lowest
effective dose
• OHSS – small risk
• Ov. Ca
• ed risk with > 12 cycles
• to recommend for –
no more than 6 cycles
Results
• induces ovulation
- 70 – 85%
• cumulative preg. Rate (6 m)
- 40 – 60%

Aromatase Inhibitors
• Letrozole – (2.5 – 7.5 mg/d)
• Anastrazole – (1mg/bd)
• 3rd generation AI
• Non-steroidal, potent and
selective
(first drug of choice / alternate to CC)

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. Anu Test Tube Baby Centre

Advantages of AI over CC
• Does not deplete ERS throughout the body
• Keeps H-P axis intact
• Short acting
 Improved endometrial thickness and
cervical mucus
 Monofollicular and better folliculogenesis

Aromatase inhibitors
- Endometriosis &
adenomyosis
- Uterine fibroids
- Endometrial stromal
sarcoma
‘MOST BENEFIT’
E2 dependent disorders
- Endometriosis
- Breast ca.
- Inherent clotting
abnormality
Luteal phase aromatase inhibitors
- drastically reduces E2 levels
- potential use in egg donors and in high risk of OHSS

Contra indications
• Ovarian failure
• untreated Hyperprolactinaemia
• uncontrolled thyroid, adrenal function
• Pituitary tumours
• Ov. Cysts
• Lack of appropriate monitoring, patient
cooperation or trained personnel
2nd line treatment for O.I
Gonadotrophin therapy
Indications
• Hypothalamic pituitary
dysfunction
• Hypogonadtropic
hypogonadism
• CC failures
• UI
• ART

Gonadotrophins Increase the no. of
follicles recruited into the growing pool
+
Maintains their growth until
the stage of ovulation
One or more oocytes are available
for fertilisation
Gonadotrophins

Mechanism Of Increased Ovulation
Rate
• Rescuing of follicles undergoing
early atresia
• Recruitment of smaller healthy
follicles
• Reduced follicular atresia

Different Gonadotropin prep.
FSH LH
activity content activity content
hMG 75 IU 75 IU
pFSH 75 IU 1 IU
HP FSH 75 IU < 0.1 IU
Recombinant
r-hFSH follitropin-a 75 IU 0
r-hFSH follitropin-b 50-100 IU 0
r-hLH 0 75
Corifollitropin α
r-hCG

‘Which preparation to use’
Recombinant drugs
•  allergic reactions
•  potential risk of
infection
• High specific activity:
less acid isoforms
• Sub-cutaneous
administration
• HMG, purified urinary
FSH & recombinant
FSH
- equally effective
• choice depends on
• availability
• user’s convenience
• cost

Dilemmas Are :
Consider –
• BMI
• AFC
• Previous
responses
What
dosage
5th, 6th & 7th day
7th & 8th day
3rd & 8th day
5th & 7th day
(alt.days)!
When
to start
No set
protocols

‘Which Gonadotrophin To Use’
• FSH – represents
‘primum movens’
of follicle growth
• LH – autonomously
& in synergy with
FSH to
Stimulate support
foll. development
& function
• HMG – Hypogonadotropic
hypogonadism
• FSH – for PCOS
• CC + FSH / HMG – preferably
•Ovulation trigger
• Luteal support
Regimens
step step combined
up down
HCG
GnRH-a

Step-up Regimen
Step-down Regimen

Ovulation Induction – GnRH analogues
+ HMG
(agonists / antagonists)
• As a routine in
most IVF centres
• Severe PCOS
• Poor responders to
HMG
• Premature LH
surges

Gonadotrophin - Risks
OHSS
Mild severe
3-2% 0.4-4%
• strictly speaking – OHSS
can not be prevented
• Adopt low dose regimens
• GnRH-a triggering
• Luteal support – prog.
• cycle cancellation
• GnRH–ant.
• cabergoline 0.5 mg/d
- 8 d. from HCG
High order
Multiple preg.
Ways to aggressive
reduce cancellation
policy
• monovulatory cycles
Heterotopic preg.
• ectopic preg – 1.5 – 2%
- with O.I – 3%
• Heterotopic preg.
- with O.I & ART– 1%

Gonadotrophins – points to be considered
i. Cost of intervention
ii. Expertise required for use of intervention
iii. Degree of intensive monitoring required
iv. Implications of multiple preg & risk of OHSS
v. The most ‘cost-effective’ gonadotrophin should
be used –
no significant difference in effectiveness
between preparations

Luteinized unruptured follicle (LUF)
Failure of follicle to rupture at expected phase
(follicular-Luteal transition)
HOW COMMON
• LUF syndrome ‘highly repeatable’ (79 – 90 %)
across cycles resulting in rec. anovulation
• Affects upto 23 % of
women with normal
menstrual cycles and
• Upto 73 % with
endometriosis

LUF – a subtle cause
• Occurrence linked to
• UI
• Endometriosis
• Pelvic adhesions
• Use of NSAIDS
• Exclude hyperprolactinaemia,
Hypothyroidism
(ovarian reserve)
• Ovulatory dysf. In POI
• Consecutive stimulation with CC

CC with or without IUI
CC alone
CC + IUI
Options
Cost
Female
partners
age
Duration of
infertility
Factors
to
Consider
A cochrane review (1159 participants)
no clinical benefit of CC for UI

CC + IUI
• Superior to spontaneous
attempts in UI > 2yrs
duration
• Increasing female age and poor
semen parameters - Lower
success rates More aggressive
treatment warranted
What Next ?
Gonadotrophin – IUI cycle or
Move on to IVF

IUI + COH
• Widely used before resorting to more
invasive options like, IVF
• COH may correct subtle ovulation
problems slightly no. of oocytes
available for fertilization
• Cochrane review (2012) –
IUI + COH increases LBR more than
2 fold compared with IUI in natural
cycle

*
• 38 – 39 yrs –
6.1 % live
birthrate /
cycle
• No live births
after 2nd cycle
*
*
• ≥ 40 yrs –
2 % per
cycle
• No live
births after
1st cycle
Success Rates in HMG + IUI cycles:-
38 – 40 yrs.
Older women – “don’t have UI”

IUI / IVF
NICE GUIDELINES, 2013 :
recommends not routinely
offering IUI to couples with
unexplained sub-fertility but
proceeding directly to IVF after
2 yrs of sub-fertility
ASRM GUIDELINES :
suggest a
progressive approach
starting with IUI
and then IVF
* However, ‘success of IUI depends on
multiple factors and many clinicians
continue to provide IUI plus COH for UI
despite Nice recommendations

Conventional Vs
Accelerated Treatment
CONVENTIONAL
TREATMENT
• 3 cycles of CC with
IUI
• 3 cycles of
Gonadotrophin
with IUI
• ≤ 6 cycles of IVF
ACCELERATED OR FAST
TRACK TREATMENT
• 3 cycles of CC + IUI
• IVF
• Median time to preg.
3m. faster
Couples in accelerated arm conceived more quickly and PR were
higher than those in conventional arm

Conclusions
• Treatments to be individualized
• Expectant management
• Low cost
• Lowest cycle fecundity rate
*Option in young women and with good ovarian reserve
*Impatience on the part of practitioners and couples frequently leads to
overtreatment
• 3 – 4 cycles of IUI & OI with Gonadotrophins
• Benefinicial for suitable couples
• IVF – should remain 1st choice only for those with
• Long duration of subfertility
• Ov. Reserve deteriorating or
• When conservative treatment failed
Treatment of choice when less expensive and simple modalities failed

Summary
 Progress from low tech to high
tech options
 Definite need for multicenter trials
to identify best treatment option
in Unexplained infertility
Anu Test Tube Baby C

Ovulation Induction Protocols for Unexplained Infertility

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