‘ President’s Medal’ for best medical graduate 1970-75

‘Dr. B.C Roy’s award’ 1999 for outstanding contribution towards medicine

‘Vikas Ratan Award’ 2002 by Nations economic development & growth society

‘Chitsa Ratan Award’ 2007 by International Study Circle

‘Life time Medical excellence award’ Obs & Gyne by Hippocrates foundation 2014

‘Abdul Kalam gold medal’ by Global Economic Progress & Research Association

2015

Course director for post doctoral Fellowship in Reproductive Medicine by NBE

since 2007 and by FOGSI for advanced infertility training since 2008.

Member of Editorial board of ‘IVF Worldwide’, Peer reviewer for ‘Journal of Human

Reproductive Sciences’, Member of advisory board for ‘Journal of Fertility Science

& Research’ and consultant advisor for queries to NDTV.com

Chairperson of Infertility sub-committee , AOGD; 2007-09

Past President of the Indian Fertility Society; 2008-10.

Field of interest: Infertility, ART, Reproductive endocrinology, Endoscopic surgery

for pelvic resurrection. and ART.

Prof. Dr. Abha Majumdar

Director, Center of IVF and Human Reproduction

Sir Ganga Ram Hospital, New Delhi, INDIA

Ovulation induction and its monitoring in Gonadotropin resistant PCOS

Prof. Abha Majumdar, Director, Centre of IVF SGRH

New Delhi

Ovulation disorder in PCOS

• Infrequent Ovulation/Oligo-ovulation

• Complete absence of Ovulation/Anovulation.

PERIPHERAL

Insulin resistance

OVARY

Hyper-androgenism

PIT-HYPOTHALAMUS

LH hypersecretion

Various theories postulated for ovulation disorder in PCOS

We encounter a complete spectrum of ovulatory dysfunction in PCOS

Generally these women are not absolutely infertile but sub-fertile

Respond to small or standard doses of Clomiphene

Exaggerated response to CC

Respond/ hyper-respond to small incremental doses of FSH

Resistance to clomiphene

Resistant to incremental doses of FSH

Respond/hyper-respond to only high doses of FSH or hMG

Monitoring with CCfirst line OI

CC day 3 to day 7

Day 3 of menses Baseline ET and ovary

Day 12 or 18 of menses dominant follicle & ET

Ovulation will follow

Progesterone< 1 ng/ml on day 18 to 25

after 7 days

Progesterone withdrawal

no dominant follicle

OR

Monitoring with FSHCC resistant PCOS

Daily inj. FSH 75 from day 3 till ovulation

Day 3 of menses Baseline ET and ovary

Day 6 of stimulation follicle & ET

After every 3-5 days to prevent hyper-response

18 to 25 days of incremental 25-50 iu FSH- no increase in follicle size or in E2 levels (> 30pg from base) think of RESISTANT PCOS

Desired response in PCOS

18 to 25 days of incremental 25-50 iuFSH no increase in follicle size and E2 30pg from baseline

RESISTANT PCOS

Problems in such cycles:

I. Follicles do not increase in size nor the E2 levelsII. Endometrium continues to be lowIII. Intermittent bleeding sometimesIV. Injections for 18 to 25 days with no change seenV. Confidence of patient and clinician go downVI. Hyper response when dose is jumped up

There exists a definite group of anovulatory PCOS, who appear to be resistant to ovulation induction when treated with small incremental doses of FSH over time for the purpose of OI.

OBESITY BMI

AMH

high LH

ANDROGENS

Studied underlying characteristics of a subset of PCOSwomen requiring stimulation of ovulation with highdoses of FSH/hMG after not having responded tonormal dose step up regimes of FSH

• Prospective study

• Centre: IVF Centre, SGRH, New Delhi

• No of patient (n) = 18 ( 6 months duration)

• Selected from a cohort of clomiphene resistant womenundergoing FSH stimulation for ovulation induction

Series of 18 cases of Clomiphene resistant Anovulatory Women with Poly Cystic Ovary Syndrome

Ovulation induction

Ovulation induction

Why don’t some PCOS respond to exogenous FSH when administered in appropriate doses for OI?

Very high AMHInhibitory effect on

follicular recruitment. Especially on low dose

step up FSH administration.

FSH receptor polymorphism

Makes follicles resistant to lower

doses of FSH. Higher doses of FSH are

required to overcome this.

Very high AMH

FSH receptor polymorphism/ v beta LH gene mutation

Frequency of FSH-R Ser680 variant is

high in hypo-responders with good OR

and consumption of FSH is higher in

carriers of this polymorphism

v-beta LH is a common genetic variant

of LH beta-sub-unit gene & is

associated with higher exogenous

FSH consumption during COH

Alviggiet al., Reproductive sci. 2015,C Alviggi, - Reproductive …, 2013 - rbej.biomedcentral.com

NO

N IV

F O

I Ovulation induction where small incremental doses of FSH used show resistance to FSH due to high AMH or FSH receptor polymorphism

CO

S FO

R IV

F COS for IVF where higher doses of FSH are used from beginning, may overcome the inhibitory effects of high AMH or the FSH receptor polymorphism.

Résistance to FSH in PCOS

Resistant PCOSGood news for IVF clinicians

Inhibition to dominant follicular selection is imposed by

Very high AMH FSH receptor polymorphism V beta LH gene mutation

over come by high doses of FSH/hMG

• Ovulation induction with CC & exogenous FSH preparationsare commonly used as first- and second-line therapy foranovulatory PCOS.

• Ovarian response to CC or FSH is hampered by limitedcontrol due to large inter & intra-individual variability.

• The outcome of ovulation induction in PCOS appears todepend, in part, on the pharmacologic compounds used butalso on individual patient characteristics, such as BMI, veryhigh AMH levels or genetic predisposition

• Such PCOS require longer duration and higher doses ofgonadotropins to have ovulatory response and often tend tohyper-respond.

Take home message

Director Centre of IVF and Human Reproduction