Transcript Is there a place for antagonist in all indications of ART?

Prof. Dr. Abha Majumdar
Director and Head
Center of IVF and Human Reproduction
Sir Ganga Ram Hospital, New Delhi,
INDIA
‘President’s Medal’ for best medical graduate 1970-75.
‘Dr. B.C Roy’s award’ in 1999 for outstanding contribution towards medicine and
field of specialty,
‘Vikas Ratan Award’ by Nations economic development & growth society 2002
‘Chitsa Ratan Award’ by the International Study Circle , 2007
Felicitated by Agra medical college for ‘Outstanding contribution towards field of
specialty. 2008
Appointed by National Board of Examination as course director to award post
doctoral Fellowship in Reproductive Medicine since 2007, and by FOGSI for basic
as well as advanced infertility training since 2008
Member of Editorial board of ‘Worldwide IVF’ and peer reviewer for ‘Journal of
Human Reproductive Sciences’
Over 15 publications in indexed journals and 20 chapters in textbooks for ob/gyn
and reproductive medicine, delivered more than 250 guest lectures and orations in
national and international conferences.
Been part of team of doctors responsible for the first IVF baby born in 1991 and the
first frozen oocyte baby born in 2009 in Northern India
Individualized controlled
ovulation stimulation (iCOS)
Prof. Dr. Abha Majumdar
Center IVF and Human Reproduction
Sir Ganga Ram Hospital New Delhi
INDIA
Nobel Prize winner: The work of British physiologist
Robert G. Edwards waited longest to be recognized.
His award for medicine comes 32 years after he figured
out how to create the beginnings of human life outside
the uterus through in vitro fertilization.
IVF started to develop fast with the aim of
maximizing pregnancy rates per cycle
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Higher number of oocytes
and thus more embryos
Use of unphysiological high
doses of gonadotropins
Time consuming protocols
Higher costs
Patient discomfort
Higher risk of OHSS
Very high risk of multiple
gestation
Rapid progression of
protocols and technology
This magic wheel had to slow down
Definition of success in IVF started shifting
from pregnancy rate per cycle towards
achieving healthy singleton child per started
course of treatment.
For achieving this
aim the first change
had to be in the
stimulation protocols
with the aim of:
•Less oocytes
•less pain /stress
•less cost
•Less complications
•Obtaining a good
oocyte / embryo/
implantation rate
Further progression of
technology aimed at
minimizing complication
rate yet maintaining
optimal pregnancy rates
Progression of technology
Past stimulation protocols
Conventional regimes
Aims at >8 oocytes but high
complication OHSS
Present milder stimulation protocols
Mild stimulation regimes
Aims at < 8 oocytes but needs
very good lab conditions
Future stimulation protocols
Individualized COS (iCOS)
Best live birth rate with
low complication; OHSS
What does iCOS mean?
A cycle with ovarian stimulation which gives
the couple best chance of singleton
pregnancy with lowest or no risk of OHSS
and minimal chance of cycle cancellation
(what ever the underlying diagnosis may be for
which the couple has to undergo IVF)
Optimization of controlled
stimulation protocols
depend upon:
Type of response expected
Age
Weight
Ovarian reserve test
Previous response to stimulation
Hormonal imbalance
PCOS/LH hyper-secretion
Hypo-gonadotropic hypogonadism)
Underlying pathology for IVF
Severe endometriosis
Male factor
Oocyte donor
Preferences for mild
stimulation
Time constraints of patient
Oncologic or pro-thrombotic
conditions requiring low
estrogen exposure in COS
Type of response expected
Age
Weight
Ovarian reserve test (ORT)
Previous response to stimulation
Regular cycles
Normal built
Age < 37
FSH <12miu/ml
AMH 10- 25pmol/l
AFC =7 to 11
Previous normal
response
Poor responder
Underlying PCOS
Thin built
Age < 30
FSH < 8miu/ml
AMH> 25pmol/l
AFC>12
Previous hyper
response
Normal responder
Hyper responder
Identifying response
Regular or
shortening cycles
Obese
Age >37
FSH > 12miu/ml
AMH<5pmol/l
AFC < 6
Previous poor
response
Optimizing treatment protocols
for normal responder
• Long protocol (GnRH agonist down regulation
followed by gonadotropin = 75 to 225 iu/day)
•Antagonist protocol (flexible / fixed protocol)
•Short agonist protocol
Optimizing treatment protocols
for high responder / PCOS
• Antagonist protocol (fixed dose regime preferred)
•Short agonist protocol
•Long protocol
•Minimal stimulation protocols with clomiphene
citrate and gonadotropins
All protocols require low starting dose of FSH 75 -150
IU/day
Optimizing treatment protocols
for poor responder
• GnRHa long protocol
•Conventional protocol
•GnRH agonist ‘stop’ or ‘mini’ dose protocol
•Antagonist protocol with flexible regime
•Short agonist protocol
•Flare agonist with antagonist with flexible protocol
(pre treatment: ocp 14 -21 days or antagonist 0.25mg/day
from day 25 or estradiol valerate 4mg /day from day 22 of
previous cycle for better cohort)
•Milder stimulation regimes
•Higher dose of FSH 150 to 300units per day
•Add LH or HMG to FSH
The Cochrane database of systemic reviews 2008
Treatment protocols for poor
responders
6 comparison groups (9 trials analyzed)
Stop protocol vs. conventional GnRHa long protocol
GnRH antagonist vs. conventional GnRHa long protocol
Bromocriptine rebound protocol vs. GnRHa long protocol
GnRHa short protocol vs. GnRHa long protocol
GnRH antagonist vs. GnRHa short protocol
Low dose flare protocol vs. spontaneous natural
The Cochrane database of systemic reviews
2008
Summary of results in poor responders
There is insufficient evidence to support the routine
use of any particular intervention for ovarian
stimulation or adjuvant therapy.
Evaluation of interventions proposed have been
performed in single, under-powered studies, which
might not have allowed the detection of the true
effect of the intervention.
More robust data from good quality RCT’s with
relevant outcomes are needed.
Hormonal imbalance
PCOS/LH hyper-secretion
Hypo-gonadotropic hypo-gonadism
PCOS with LH hypersecretion
Ignore basal high LH levels and start with
antagonist protocol
Down regulation with GnRH agonist followed by
stimulation with gonadotropins (FSH)
Basal LH inhibition with antagonist for 2 days
then stimulation with gonadotropins/antagonist
protocol
Pre treatment with oral contraceptives for 1 to 3
months or ovarian drilling
Hypogonadotropic
hypogonadism
LH control not required no need of agonist or
antagonist
Step up regime with HMG is the ideal treatment or
rec FSH with rec LH
Luteal support mandatory with hCG as well as
progesterone.
Underlying diagnosis
Severe endometriosis
Male factor
Oocyte donor
Severe endometriosis
Meta analysis ESHRE 2005
ESHRE guidelines for endometriosis 2008
Administration of GnRH agonists for 3–6 months prior to
IVF in patients with endometriosis increases clinical PR (4
fold) and the live birth rate significantly (9 fold).
Cochrane data base systemic review 2006
Long term down regulation for 60 to 90 days before IVF
for women with endometriosis is better than long
protocol: 3 RCTs with 165 women (Evidence level 1b)
Live BR/ woman OR 9.19: Clinical PR: OR 4.28
Male factor infertility
Stimulated as per the response
of female partner expected
hyper - responder
normal - responder
poor-responder
Optimum stimulation for
Oocyte donors
Donors for oocytes undergoing
ovarian stimulation
Improved donor satisfaction is likely to improve
donor recruitment and retention
Minimizing trips to the clinic; protocols to limit
number of I/M injections; reduced risk of OHSS
Reimburse expenses for lost work, travel, and
child care; want to be treated with respect and
appreciation;want information about outcome.
A qualitative follow-up study of experiences with oocyte donors; A.L.
Kalfoglou; Hum. Reprod. (2000) 15 (4): 798-805.
Gonadotropin-releasing hormone agonists versus
antagonists for controlled ovarian hyperstimulation in
oocyte donors: a systematic review and meta-analysis
Daniel Bodri; Fertility and Sterility, Volume 95, Issue 1 , Pages
164-169, January 2011
No differences after donor stimulation with GnRH
antagonist protocols (compared to long agonist)
on number or quality of retrieved oocytes or
ongoing pregnancy rate.
USG follicle monitoring enough for follow up of
donor cycles with antagonist protocol (serum E2 not
necessary and lesser days of injections).
GnRH agonist trigger safe treatment option for
egg-donors. No compromise on embryo quality
and risk of OHSS reduces considerably.
GnRH antagonist protocol with agonist trigger
appears best for oocyte donors
Anna Galindo, January 2009, Vol. 25, No. 1 , Pages 60-66
 A. Sismanoglu et al, J. Assist Reprod and Genetics, 26; 5, 251-256
 M Melo et al, ReprodBioMedOnline,19; 4, October 2009, 486–492
 J.C. Castillo et al, Reprod BioMed Online, Nov. 2011

Preferences for mild
stimulation
Time constraints of patient
Oncologic or pro-thrombotic
conditions requiring low
estrogen exposure in COS
The ISMAAR proposal on terminology for ovarian
stimulation for IVF
Preferences for mild stimulation
and for couples with time
constraints
Conventional antagonist protocol
Natural cycle or modified natural cycle
IVF with counseling for single oocyte
Pro-thrombotic or Oncologic issues
requiring low E2 during COS
(estrogen sensitive malignancy: breast or endometrium)
 Mild stimulation regimes
 Letrozole daily with conventional doses of
gonadotropins till hCG or GnRH agonist
trigger ( aim is to keep E2 <500 pg /ml with
dose of letrozole as high as 10mg/day)
Cakmac H et al; Fertility Sterility; Vol 100, No. 6 Dec 2013
Fertility preservation before
cancer therapy
Protocols with alternative timing
 Luteal phase: Initiate luteolysis with 0.25mg
antagonist for 2-3 days followed by COS.
 Random start: late follicular phase or luteal
phase- start gonadotropins as per patient
profile, add antagonist when secondary
cohort >12 mm size, trigger hCG/agonist
 2 consecutive stimulations in one menstrual
cycle to maximize embryo preservation
Cakmac H et al; Fertility Sterility; Vol 100, No. 6 Dec 2013
Turan V et al; Fertility Sterility; Vol 100, No. 6 Dec 2013
Summary of Pre-requisite for iCOS
Prospective identification of ovarian response
II. Determine co-existing hormonal imbalances affecting COS
III. Determine underlying pathology which could change the
need for protocol for optimal iCOS
IV. Ensure complete safety for oocyte donors without
compromising on oocyte quality
V. Adopt protocols to fit the need of an individual patient as
per time available to her for an ART cycle
VI. Respect a woman’s desire of minimal stimulation
VII. ICOS for patients with oncologic issues with urgent need
for oocyte or embryo cryo preservation.
VIII. Pro-thrombotic conditions or oestrogen dependent cancers
at risk with high oestrogen levels during COS
IX. Optimizing total reproductive potential of a couple by use of
embryo cryopreservation technology.
I.
ICOS in ART for maximizing
success would eventually
mean?
A cycle with ovarian stimulation which
gives the couple best chance of
singleton pregnancy with lowest or no
risk of OHSS and minimal chance of
cycle cancellation (what ever the
underlying diagnosis may be for which the
couple has to undergo IVF)
OVULATION INDUCTION
IS NOT ONLY A SCIENCE
BUT ALSO AN ART