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‘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. 2008Appointed 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 2008Member 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
Prof. Dr. Abha MajumdarDirector and HeadCenter of IVF and Human ReproductionSir Ganga Ram Hospital, New Delhi, INDIA
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Individualized controlled ovulation stimulation (iCOS)
Prof. Dr. Abha MajumdarCenter IVF and Human ReproductionSir Ganga Ram Hospital New Delhi
INDIA
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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.
Single oocyte
Single embryo
Single baby
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IVF started to develop fast with the aim of maximizing pregnancy rates per cycle
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
technology
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This magic wheel had to slow down
tech
nology
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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
technology
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Future stimulation protocols
Individualized COS (iCOS) Best live birth rate with low complication; OHSS
Present milder stimulation protocols
Mild stimulation regimes Aims at < 8 oocytes but
needs very good lab conditions
Past stimulation protocols
Conventional regimes Aims at >8 oocytes but high complication OHSS
Progression of technology
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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)
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Type of response expected
Age
Weight
Ovarian reserve test
Previous response to stimulation
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
Hormonal imbalance
PCOS/LH hyper-secretion
Hypo-gonadotropic hypo-gonadism)
Optimization of controlled stimulation protocols depend upon:
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Type of response expected
Age
Weight
Ovarian reserve test (ORT)
Previous response to stimulation
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Hyp
er r
espo
nder Underlying PCOS
Thin built
Age < 30
FSH < 8miu/ml
AMH> 25pmol/l
AFC>12
Previous hyper response N
orm
al r
espo
nder
Regular cycles
Normal built
Age < 37
FSH <12miu/ml
AMH 10- 25pmol/l
AFC =7 to 11
Previous normal response
Poo
r re
spon
der Regular or
shortening cycles
Obese
Age >37
FSH > 12miu/ml
AMH<5pmol/l
AFC < 6
Previous poor response
Identifying response
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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
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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 gonadotropinsAll protocols require low starting dose of FSH 75 -150 IU/day
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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
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The Cochrane database of systemic reviews 2008 Treatment protocols for poor
responders6 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
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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.
Summary of results in poor responders
The Cochrane database of systemic reviews 2008
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Hormonal imbalance
PCOS/LH hyper-secretion
Hypo-gonadotropic hypo-gonadism
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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
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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.
Pretreatment with estrogen and
progesterone cyclically for 6 to 9
months till the mid cycle endometriu
m
appears ideal for im
plantation.
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Underlying diagnosis
Severe endometriosis
Male factor
Oocyte donor
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Severe endometriosis
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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).
Meta analysis ESHRE 2005ESHRE guidelines for endometriosis 2008
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
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Male factor infertility
Stimulated as per the response of female partner expected hyper - responder
normal - responder
poor-responder
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Optimum stimulation for Oocyte donors
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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.
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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).
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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
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Preferences for mild stimulation
Time constraints of patient
Oncologic or pro-thrombotic conditions requiring low estrogen exposure in COS
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The ISMAAR proposal on terminology for ovarianstimulation for IVF
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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
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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
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Fertility preservation before cancer therapy
Protocols with alternative timingLuteal 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 2013Turan V et al; Fertility Sterility; Vol 100, No. 6 Dec 2013
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I. 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.
Summary of Pre-requisite for iCOS
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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)
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OVULATION INDUCTIONIS NOT ONLY A SCIENCE
BUT ALSO AN ART
OVULATION INDUCTIONIS NOT ONLY A SCIENCE
BUT ALSO AN ART