AN IDEAL OVULATION

INDUCTION REGIMEN
 Types of ovarian stimulation

• Ovulation induction

• Superovulation

• Controlled ovarian hyperstimulation

 OVULATION INDUCTION

The goal
to develop follicles in anovulatory cycles as in PCOS and in
hypogonadotrophic hypogonadism

PCOS-aim for monofollicular development

 SUPEROVULATION

Intentional production of more(≤ 4 ) mature follicles in a patient

with:
• unexplained infertility
• Minimal and mild endometriosis
• Mild male factor infertility
 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
 Drugs In Ovarian Stimulation
• Clomiphene citrate and Tamoxifen
• Letrozole/Anastrozole
• Gonadotropins
• GnRH analogues
• GnRH agonists
• GnRH antagonists
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
 Long follicular
Gn
GnRHa

1 2 14 1 2 3

hCG OPU

Agonist given from Day 2 of

previous cycle till day of trigger
 Long luteal
Gn
GnRHa

1 2 14 21 1 2 3

hCG OPU

Agonist given from Day 21 of previous

cycle till day of trigger, dose is halved
once gonadotrophins are added
 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
Short protocol

Gn
GnRHa

1 2 3

hCG OPU

• Agonist given till day of trigger

• Flare Up Effect f/b down regulation
 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.
 Ultra short protocol

Gn
GnRHa

1 2 3 4 5 6

hCG OPU
• Agonist given for 3 days
• Flare Up Effect
• Used in poor responders
 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 )
 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
CETRORELIX - 3 mg hCG

The antagonist is administered on day 5 / 6 of stimulation

 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
 Definition

Human Reproduction, Sept,2007.

 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 IVF:FSH 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.
Agonist vs Antagonist vs Mild
 Kato Protocol DF >18 mm
E2 >300 pg/mL/Oocyte
No need for adding
antagonist as clomiphene
prevents premature LH surge

GnRH agonist
trigger D2 ET

Clomiphene Citrate OPU

32-35 Hrs
50 50 50 50 50 50 50 50 50

FSH 150 150 150

D3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
S Teramoto, O Kato; Minimal ovarian stimulation with CC: A Large-scale retrospective
Study: RBM Online: Volume 15, No 2, August 2007
 LETROZOLE IN SOFT STIMULATION

hCG

Step Up Letrozole
ET
2.5 5.0 7.5 10.0 FSH OPU

Ultra Flare
150 150 150 150 150
GnRHa

D3 4 5 6 7 8 9 10 11 12 13 14 15

Antagonist 0.25 mg sc/day

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

ENDOMETRIOSIS
 Various protocols that are beneficial in POR

• Mild stimulation
• Short agonist
• Microflare
• Shanghai protocol
 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
• RCT’s are required to evaluate the outcome
Double Stimulation protocol

2nd phase of stimulation if atleast 2 AFC (2-8 mm) post OPU

 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.
 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
 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
 Individualised controlled ovarian stimulation (iCOS):
maximising success rates for assisted reproductive
technology patients
Bosch 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