In Vitro Fertilization (IVF) ovarian stimulation protocols - Assisted reproductive technologies

Dr. Anuradha Katragadda
ANU TEST TUBE BABY CENTER

IVF REGIMENS
 Different approaches to ovarian
stimulation
 Oocytes collected in Natural and
Stimulated cycles

I - IVF BABY
 Birth of Louis Brown – July, 1978
‘Steptoe & Edwards’, the pioneers
of In-Vitro-Fertilization (IVF)
 Result of a single oocyte
retrieved in a natural cycle

REVOLUTION / EVOLUTION –
OVARIAN STIMULATION DRUGS
 Ovarian stimulation
 An integral part of ART
 Each phase had -
 Own ‘gold standard’
stimulation
 A large armamentarium of
pharmaceutical agents
 To utilise in treatment
protocols
The initial regimens:
clomiphene citrate.
Urinary gonadotropins were later
added to the ovulation induction
regimen alone or in combination
with clomiphene citrate.
In the late 1980s- early 1990s:
addition of a GnRH agonist to
achieve pituitary modulation.
1990s-
Development of Recombinant
Gonadotrophins, GnRH
antagonists.

STIMULATION REGIMENS –
‘WHAT TERMINOLGY’
 ‘International society for mild
approaches in Assisted
Reproduction’(ISMAAR)
Revised definitions & terminology
for natural cycle & different
protocols for stimulation

MODIFIED / NATURAL CYCLE IVF
 Aim – to collect a naturally selected
single oocyte at the lowest possible cost
LH surge
DF OR
0 10 14 28
Days
0 10 14 28
HMG / FSH
± GnRH-ant.
OR
15 mm
HCG
Days

‘PROS’ & ‘CONS’ OF NATURAL CYCLE IVF
ADVANTAGES : DISADVANTAGES :
• simple
• Less invasive
• Less stressful
• Can be repeated
every month
• No risk of
OHSS
• Higher
cancellation rates
• Lower pregnancy
rates
• Need for
monitoring LH
surge

HMG
GnRH ant.
CC
MILD IVF
0 7 14
Days
3
OR
HCG
F – 14 mm
‘ This method is likely to increase and possibly
even replace the current conventional protocol
in future’.

‘WHY-CONVENTIONAL PROTOCOLS’
(to tackle premature LH Surge)
Gonadotropins used to stimulate follicle growth
1
Stimulation of many follicles results in higher E2 levels
2
LH surge occurs before complete follicle maturation
3
Developmental arrest of oocytes and cycle cancellation
4

CONVENTIONAL IVF
(GnRH – analogue cycles)
PROTOCOL
i. GnRH-agonist - used for pituitary
downregulation followed by
conventional doses of stimulation with
FSH or HMG
ii. GnRH-antagonist - With conventional
doses & early start of FSH / HMG

Schematic graph showing first treatment protocol for IVF

GnRH ANALOGUES
Generic Dose
Goserelin 3.6 mg/mth
Buserelin 6.6 mg/6wks
300 mcg tds
Leuprorelin 3.75 mg/mth
1 mg/ml
Triptorelin 3.75 mg/mth
0.1 mg/day
Nafarelin 400 mcg/day

GnRH–a PROTOCOLS
FSH / HMG
GnRH agonist
GnRH agonist
HCG
D - 2
D - 21
D - 3
SHORT PROTOCOL
LONG PROTOCOL

GnRH – a PROTOCOLS
ML GnRH–a
 Suppression more
prompt
 Fewer cystic
follicles
Flare Protocol
 Shorter duration
 Fewer injections
 Lower gonadotrophin
dose

ALTERNATE REGIMENS
 ‘Ultralong’ GnRH-a
 3-6 m. depo-agonist in stage III – IV
endometriosis before IVF
 PR higher
 ‘Mini dose’ GnRH-a
 For poor responders
 Lupron 0.25mg/d followed by 0.1 mg/d
from stimulation
 OC / GnRH-a
 For high responders
 OC for 25 days and 1mg Lupron from last 5
days

 Third generation decapeptide
 GnRH agonist with amino acid
modifications at 1,2,3,6 & 10
2 Compounds 2 Regimens
Cetrorelix Flexible
Ganirelix Fixed
GnRH ANTAGONISTS

COS - Complications
Multiple Pregnancy
Increased incidence of heterotopic
pregnancies
OHSS

ECTOPIC & HETEROTOPIC
PREGNANCIES
 Incidence of ectopic – 1.5 - 2 %
 With Ovulation Induction - 3 %
 With ART - 5 %
 Incidence of Heterotopic Pregnancies –
1 in 30,000
 With Ovulation Induction & ART – 1 %
 Surgical treatment – viable option
 1/3rd spontaneous miscarriages
 A high index of suspicion required

OHSS
‘ Loss of control over COH ’
 Only after overstimulated ovaries
‘ exposed to hCG inj ’
C U L P R I T
HMG HCG

OVARIAN HYPERSTIMULATION
 An iatrogenic complication
 Significant increase globally
 Incidence of moderate cases ≈ 5 %
 Incidence of cases requiring admission
hospitalization ≈ 2 %
Devastating consequence of OHSS is a serious
threat to life –
3 maternal deaths 100,000

BEFORE STIMULATION
PREDICTING RISK PREVENTION STRATEGY
RISK FACTOR THRESHOLD
1. Age < 33 yrs
2. BMI < 19
3. Previous moderate / severe
H/o OHSS & H/o Hospitalization
4. PCO ≥ 12 AF 2-8 mm
diam.
5. High AFC > 14
6. High Basal AMH > 8 mg / ml
1. Exposure to mild stimulation
gonadotrophins low dose protocols
No FSH on
day of hCG
2. GnRH antagonist risk
protocol
3. Metformin / Glucocorticoids

DURING STIMULATION
PREDICTING RISK PREVENTION STRATEGY
RISK FACTOR THRESHOLD
1. No. of follicles on > 14 follicles with
day of hCG diam. Of 11mm.
2. Levels & rate of > 3,000 pg / ml
of E2
3. Elevated inhibin levels
on d 5 of gonadotrophins
& 3 d before OPU
1. hCG for trigger requires large RCT
2. Coasting appears to reduce
but does not
eliminate
3. Alternative agents
for trigger GnRH-a
4. Dopamine Agon- reduced incidence
ists
5. Unilateral ovarian
follicular aspiration
6. ‘ cycle cancellation’.

OHSS - FUTURE
 Design individualized treatment
protocols
 In-Vitro maturation of oocytes
Artificial ovary
 ‘ Mild ’ stimulation for IVF
 Single embryo transfer (SET)

IN-VITRO-MATURATION (IVM)
 Collecting immature oocytes from hormonally
unstimulated or minimally primed
follicles to achieve a live birth
 Immature oocytes are collected from small
antral follicles before spontaneous
ovulation,
Matured in lab. For 24 – 48 hrs. using
culture medium with added small quantities of
hormones. Routine IVF / ICSI
 IVM reduces risks & costs associated with COS

IVM - INDICATIONS
 PCOS – most widely used indication
 Young women with high AFC
 Overresponders to Gonadotrophins
 Poor responders
 Empty follicle syndrome
 Oocyte donation
 Fertility preservation

CONCLUSIONS - IVM
 Not a competitor of IVF; a
complementary ART
 Simplest & least invasive option
 With further improvements can be
come – ‘Ultimate’ patient-
friendly protocol

AN OHSS – FREE CLINIC
Segmentation –
of –
IVF treatment

Segmentation of IVF
OHSS can be ‘erased’ by applying ovarian
stimulation using a combination of
GnRH-antagonist with
GnRH-agonist trigger
- freeze all

AGONIST - TRIGGER
 Possibility of luteal phase defect
Reduced pregnancy rates
1. Rescue of luteal phase
2. ‘Freeze all’ – a safe alternative

THE PATIENT-FRIENDLY
PROTOCOL
Segmentation of IVF –
- Freeze-all &
Frozen embryo cycle
‘The balance between the desire for pregnancy
and patient’s safety is a top priority’.

Is antagon protocol-
a universal protocol
NO-ONE-SIZE FITS ALL

ENDOMTRIOSIS – IVF PROTOCOLS
 ART most effective therapy
 Inferior outcomes may result from
Decreasing no of retrieved oocytes
Reducted oocyte/embryo quality
Impaired uterine receptivity

ENDOMTRIOSIS – IVF PROTOCOLS
 3-6 months of GnRH-a treatment
-increased pregnancy rates
 Risk of pelvic infection
Resulting infected endometrioma or
pelvic abscess necessitate
surgical intervention

FERTILITY PRESERVATION
INDICATIONS –
 Cryopreservation of Oocytes / embryos
 Young women with cancer, before chemo /or
Radiotherapy
 Women who wish to circumvent the
advancing age

Controlled ovarian stimulation (cos) is a
preferred method- higher success rates
CONVENTIONAL PROTOCOL –
 Initiated at beginning of follicular phase
 Requires 2-6 wks. Depending on menstrual phase
May cause significant delay of cancer
treatment
‘potential for increased stress for patient
& physician’

RANDOM – START – COS
(FERTILITY PRESERVATION)
‘Stimulation on presentation regardless
of menstrual phase’
COS in follicular / Luteal phase –
i. Initiating Luteolysis followed by COS
with menses
ii. Initiating Luteolysis with
simultaneous COS

ESTROGEN SENSITIVE MALIGNANCY –
(i.e. endometrial or ER – positive breast ca)
 2.5 – 5 mg Letrozole started with
stimulation & continued until trigger
 Letrozole titrated upto 10 mg/d
depending on E2 levels

RANDOM – START COS
Late follicular phase :
i. Before spontaneous LH surge;
i. If follicle cohort following lead follicle < 12 mm. –
start ovarian stimulation with out GnRH – ant.
ii. If follicle cohort ≥ 12 mm – OS with GnRH-ant.
ii. After LH surge ;
GnRH–ant. When secondary follicle cohor reach 12 mm
Periovulatory phase :
- when DF 18 mm; GnRH-a or hcg trigger
stimulation started 2-3 after trigger
Luteal phase :
- ovarian stimulation started in absence of GnRH-ant.

 Creates an opportunity to attempt
fertility preservation
 A prompt referral may allow embryo or
oocyte cryopreservation without a
delay in chemotherapy

POOR RESPONDERS :
Is There Any Thing New ?
 Estimated incidence 9-24 %
 Recent reviews, shows slight increase
 Limitation in quantifying incidence
 Difficulty of a clear definition
 Substantial lack of literature that
identifies an ideal protocol

AGE – ‘POR’
 Single most important determinant factor
 Women under 35 yrs - 32.3 %
 35 – 37 yrs - 27.7 %
 38 – 39 yrs - 19 %
 40 – 42 yrs - 11.9 %
 43 – 44 yrs - 4.6 %
 44 + yrs - 4 %

DECREASE IN OVARIAN RESERVE
- CAUSES
 Ov. Surgery (especially endometrioma)
 Genetic defects
 Chemotherapy
 Radiotherapy
 Autoimmoune disorders
 Single ovary
 Ch-smoking &
 Unexplained infertility
 Diabetes mellitus Type I
 Transfusion dependent β- Thallasemia

‘THE BOLOGNA ESHRE
CRITERIA’: POOR RESPONDER
 At least 2 of the following criteria:
i. Previous episode of POR (≤ 3 oocytes
with standard dose)
ii. An abnormal ov. Reserve;
 AFC < 5 – 7 follicles
 AMH < 0.5 – 1.1 ng/ml
 Women > 40 yrs. Age or
 Presence of other risk factors for POR

IS THERE AN IDEAL
PROTOCOL ?
GONADOTROPINS
 Higher doses of Gonadotropins
 Conflicting data reported
 Recent studies
 Increase of FSH starting dose does not result
in higher PR
 No diff. between starting dose of 300, 450 &
600 IU.

GnRH-a PROTOCOLS - POR
 Decrease the length of suppression
 Decreasing duration of GnRH-agonist
Short or ultrashort
Microdose protocols
 To lower or to stop (after pit. Suppression)
the dose of initiated GnRH-a.
 To use GnRH-antagonist
May induce excessive ov. suppression

ALTERNATIVE APPROACHES - POR
Addition of estradiol in luteal phase
 Decreases risk of cycle cancellation &
increases chance of preg.
 Luteal E2 priming could improve
synchronization of pool of follicle
available to COS
Addition of Rec. LH
 Recent meta-analysis of 40 RCT –
 Significantly more oocytes with r-hFSH plus r-
hLH vs r-hFSH treatment in POR

ALTERNATIVE APPROACHES
 Addition of growth hormone (GH)
 Modulates the action of FSH on
granulosa cells by upregulating local
synthesis of IGF-1
 No recent or robust data suggesting
routine addition

ALTERNATIVE APPROACHES
 Addition of Androgens
 Inadequate levels of endogenous androgens –
associated with decreased ov. Sensitivity to FSH
lower PR
 Oral administration of DHEA
 Before ovarian stimulation could improve response
 Recent meta-analysis of 4 RCT
 Significantly higher PR
 Needs large multicentre RCT
 Addition of Aspirin
 No substantial positive effect

ALTERNATE APPROACHES - POR
 Natural cycle IVF with or without
minimal stimulation
 Easier & cheaper approach
 50 % cancellation rate
 Contradictory reports

POR remains one of the most
challenging tasks in
reproductive medicine.
Oocyte / embryo donation - POR

OOCYTE / EMBRYO DONATION
Gamete donation
- The first sperm donor insemination-
Philadelphia, in 1884
- First oocyte donation-
Monash IVF centre, 1983
‘Cross –Border Reproductive care’.
- gametes & embryos moving across borders
- individuals travelling to different countries

THE END OF DONOR ANONYMITY
 Genetic testing
 Direct-to-consumer (DTC)
 Formation of large international genetic
geneology databases
 DTC genetic testing- (commercial co.)
 ‘Family tree DNA’-
 Offers Y-DNA matching database
 ‘The 23 and Me’-
 Autosomal DNA test for males & females
-to solve unknown parentage cases

END OF DONORY ANONYMITY
 ‘uncovering secrets’
 Donor anonymity not guaranteed
 May drive gamete donation out of business

‘Fertility industry needs a critical self-
analysis to strike an ethical balance
which can allow autonomoUs informed,
decision-making for patients’

FUTURE – OVARIAN
STIMULATION PROTOCOLS
 To develop novel treatment protocols to
Reduce risk of OHSS, multiple preg
Improve oocyte & endometrial quality
Reduce emotional stress & financial
burden

In Vitro Fertilization (IVF) ovarian stimulation protocols - Assisted reproductive technologies

In Vitro Fertilization (IVF) ovarian stimulation protocols - Assisted reproductive technologies

More Related Content

What's hot

Similar to In Vitro Fertilization (IVF) ovarian stimulation protocols - Assisted reproductive technologies

More from Anu Test Tube Baby Centre

Recently uploaded

In Vitro Fertilization (IVF) ovarian stimulation protocols - Assisted reproductive technologies