AN IDEAL OVULATION INDUCTION REGIMEN

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AN IDEAL OVULATION INDUCTION REGIMEN
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Types of ovarian stimulation

• Ovulation induction
• Superovulation
• Controlled ovarian hyperstimulation

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OVULATION INDUCTION

• The goal
• to develop follicles in anovulatory cycles as
  in PCOS and in hypogonadotrophic hypogonadism
• PCOS-aim for monofollicular development

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SUPEROVULATION

• Intentional production of more( 4 ) mature
  follicles in a patient with
• unexplained infertility
• Minimal and mild endometriosis
• Mild male factor infertility

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Controlled Ovarian Stimulation (COS)

• The goal is to recruit multiple follicles that
  may yield mature oocytes, without inducing OHSS
• In general, aim is to achieve 8 to 15 follicles
  characterizes an acceptable response.
• Greater than 15 is considered a high response
• COS is done for IVF-ICSI cycles

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Drugs In Ovarian Stimulation

• Clomiphene citrate and Tamoxifen
• Letrozole/Anastrozole
• Gonadotropins
• GnRH analogues
• GnRH agonists
• GnRH antagonists

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Protocols in COS

• AGONIST PROTOCOLS
• - Long Protocol/ Stop Protocol/ Short
  Protocol/ Ultrashort Protocol/ Microflare
• ANTAGONIST PROTOCOL -Fixed/ Flexible
• Mild Stimulation Protocol / Softer protocols
• Special Cases
• - Endometriosis- Ultra Long Protocol
• - Poor ovarian reserve- double
  stimulation Protocols
• -PCOS- Stair Step and Chronic Low
  dose Step up Protocols

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Long follicular
Gn
GnRHa
1 2 14
1 2 3
OPU
hCG
Agonist given from Day 2 of previous cycle till
day of trigger
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Long luteal
GnRHa
Gn
1 2 14 21
1 2 3
OPU
hCG
Agonist given from Day 21 of previous cycle till
day of trigger, dose is halved once
gonadotrophins are added
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Long Protocols

• Protocol starts in the previous cycle (
  follicular / luteal )
• Initial Flare up effect for 3-4 days
• Followed by pituitary desensitisation and
  receptor down regulation
• Agonist continued till trigger day, ensures
  prevention of LH surge

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Short protocol
Gn
GnRHa
1 2 3
OPU
hCG

• Agonist given till day of trigger
• Flare Up Effect f/b down regulation

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Short / Flare Up protocol

• Initial Flare Up Effect increases recruitment of
  follicles augments growth
• Overall lesser amount of gonadotrophins decreased
  costs.
• Mainly used in poor responders
• Disadvantage High LH in initial part of the
  cycle
• High Androgen levels
• Benefits not
  supported by evidence.

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Ultra short protocol
Gn
GnRHa
1 2 3 4 5 6
OPU
hCG

• Agonist given for 3 days
• Flare Up Effect
• Used in poor responders

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GnRH Antagonist Protocol

• Multiple Dose Protocol
  Cetrorelix 0.25 mg S /C
• ( Long German - Lubec Protocol )
  Ganirelix 0.25 mg S / C
• Half Life - 13 Hours
• Daily Injections till the Day of HCG
• Single Dose Protocol
  Cetrorelix 3 mg S / C
• ( Short French Protocol )
• Actions lasts for 96 hours ( 3 4
  Days )

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Antagonist Protocol
CETRORELIX/GANIRELIX - 0.25 mg/day
Fixed Day Regimen
Multiple doses
hCG
r FSH/hMG
0
1
2
3
4
5
6
7
8
9
10
Cycle Day
r FSH/hMG
Single dose
hCG
CETRORELIX - 3 mg
The antagonist is administered on day 5 / 6 of
stimulation
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Antagonist Protocol
CETRORELIX 0.25 mg /day
Flexible Regimen
Multiple doses
hCG
r FSH/hMG
0
1
2
3
4
5
6
7
8
9
10
Cycle Day
r FSH/hMG
CETRORELIX 3 mg
Single dose
hCG
The antagonist is administered when the lead
follicle is 12- 14 mm, or E2 reaches 300 - 400
pg/ml
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Definition
Human Reproduction, Sept,2007.
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Definition

• Natural Cycle IVF Oocyte collected in
  spontaneous menstrual cycle without
  administration of any medication at any time in
  the cycle.
• Modified Natural Cycle Administration of drugs
  in a spontaneous cycle with the aim of collecting
  a naturally selected single oocyte but with a
  reduction in chance of cycle cancellation.
• Mild Stimulation IVFFSH or HMG is administered
  at lower doses, and/or for a shorter duration in
  a GnRH antagonist co-treated cycle, with or
  without oral compounds.

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Agonist vs Antagonist vs Mild
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Kato Protocol
DF gt18 mm E2 gt300 pg/mL/Oocyte
No need for adding antagonist as clomiphene
prevents premature LH surge
GnRH agonist trigger
D2 ET
OPU 32-35 Hrs
Clomiphene Citrate
50
50
50
50
50
50
50
50
50
150
150
150
FSH
D3
4
5
6
7
9
10
11
15
16
8
12
13
14
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S Teramoto, O Kato Minimal ovarian stimulation
with CC A Large-scale retrospective Study RBM
Online Volume 15, No 2, August 2007
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LETROZOLE IN SOFT STIMULATION
hCG
ET
Step Up Letrozole
OPU
5.0
7.5
10.0
2.5
FSH
150
150
Ultra Flare GnRHa
150
150
150
D3
4
5
6
7
9
10
11
15
8
12
13
14
Antagonist 0.25 mg sc/day
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Ultra Long Protocol for Endometriosis
GnRH Agonist for a period of 3 to 6 months
prior to treatment with ART improves Clinical
Pregnancy rates and decreases miscarriage rates
in Infertile women with Endometriosis
ESHRE Guidelines on Endometriosis Sept, 2013
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ENDOMETRIOSIS
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Various protocols that are beneficial in POR

• Mild stimulation
• Short agonist
• Microflare
• Shanghai protocol

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• Kuang et al 2014
• Antral follicles in the follicular phase and
  luteal phase recruited
• Combines two stimulation protocols in one cycle
• 2 oocyte retrievals in a single menstrual cycle
• Increase the number of oocytes and viable embryos
• RCTs are required to evaluate the outcome

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Double Stimulation protocol
2nd phase of stimulation if atleast 2 AFC (2-8
mm) post OPU
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Long gonadotropin-releasing hormone agonist
versus short agonist versus antagonist regimens
in poor responders undergoing in vitro
fertilization A RCT (PRINT) Sunkara et al, Fert
Stert Jan 2014

• Results
• Number of oocytes retrieved was significantly
  higher with long GnRH agonist compared with the
  short agonist regimen.
• Duration of stimulation and total gonadotropin
  dose were significantly higher with long agonist
  compared with short agonist and antagonist
  regimens.
• Conclusion(s) Long GnRH agonist and antagonist
  regimens offer a suitable choice for poor
  responders, whereas the short agonist regimen may
  be less effective because of fewer eggs retrieved.

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GnRH Antagonist Vs GnRH Agonist

• IVF Live Birth Rates Similar for GnRH
  Antagonist and GnRH Agonist Protocols.
• -Al Inany HG, Youssef MA, Aboulghar M, et al
  2011
• Gonadotropin releasing hormone antagonists
  for ART
• Cochrane Database, Syst Rev 11, CDOO1750
  
• May be Preferred for - Poor Responders
• -
  Women with Diminished Ovarian Reserve

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Individualised COS (ICOS)

• The main objective of individualisation of
  treatment in IVF is to offer every single woman
  the best treatment
• Tailored to her unique characteristics
• Maximizing success
• Eliminating iatrogenic risks, such as OHSS
• Minimizing the risk of cycle cancellation

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Individualised controlled ovarian stimulation
(iCOS) maximising success rates for assisted
reproductive technology patientsBosch E, Ezcurra
D Reprod Biol Endocrinol 2011 Jun

• COS in IVF - significantly improved outcomes, but
  current stimulation protocols are not optimal for
  all patient groups.
• Alternatives to standard COS protocols,
  including mild and natural cycles, have shown
  some success, but no single approach is
  appropriate for all patients in a given
  population.
• Treatment should be adapted for individual
  patients through iCOS and that, together with the
  further development of objective biomarkers of
  response, will be an important first step towards
  implementing personalised medicine in
  reproductive science

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