‘president’s medal’ for best medical graduate 1970-75. ‘dr. b.c roy’s award’ in 1999 for...

‘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

Individualized controlled ovulation stimulation (iCOS)

Prof. Dr. Abha MajumdarCenter IVF and Human ReproductionSir 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.

Single oocyte

Single embryo

Single baby

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

This magic wheel had to slow down

tech

nology

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

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

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)

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:

Type of response expected

Age

Weight

Ovarian reserve test (ORT)

Previous response to stimulation

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

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 gonadotropinsAll 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

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

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

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.

Pretreatment with estrogen and

progesterone cyclically for 6 to 9

months till the mid cycle endometriu

m

appears ideal for im

plantation.

Underlying diagnosis

Severe endometriosis

Male factor

Oocyte donor

Severe endometriosis

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

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 ovarianstimulation 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 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

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

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 INDUCTIONIS NOT ONLY A SCIENCE

BUT ALSO AN ART

OVULATION INDUCTIONIS NOT ONLY A SCIENCE

BUT ALSO AN ART