The Poor Responder – New Medical Treatment Poor Responders ...

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The Poor Responder – 

New Medical Treatment 

Prof Ehud Margalioth 

Director IVF unit 

Shaare Zedek Medical Center 

Dr. Jordana Hyman 

Poor Responders 

�� 10-15% 10 15% of women undergoing IVF have a poor response 

to ovarian stimulation 

�� Advanced maternal age 

�� Premature ovarian failure 

�� Decreased ovarian reserve due to: 

�� Genetics 

�� Surgery 

�� Endometriosis 

�� Radiation 

�� Chemotherapy 

�� affects egg production 

�� affects oocyte quality 

�� Low pregnancy rate irrespective of treatment

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How do we define a poor responder 

� AGE 

� CLINICAL 

� No of follicles : 1 - 4 , No of oocytes : 1 - 4 

� Peak Estradiol levels: < 500 pg/ml 

� Excessive requirements of gonadotropins: > 450 IU 

� TESTS 

� Basal day 3 FSH 

� CC challenge test 

� Inhibin B 

� AMH 

� Ovarian Volume 

� Antral follicle count 

Evaluation and management of low 

responders in IVF - reviews 

�� Evaluation and Treatment of Low Responders in Assisted Reproductive Reproductive 

Technology 

SOZOS J. FASOULIOTIS, ALEX SIMON, and NERI LAUFER 

Journal of Assisted Reproduction and Genetics, Vol. 17, No. 7, 2000 

� Clinical management of low ovarian response to stimulation for IVF: a systematic review 

B.C.Tarlatzis1, L.Zepiridis, G.Grimbizis and J.Bontis 

Human Reproduction Update, Vol.9, No.1 pp. 61±76, 2003 

� Interventions for ’poor responders’ to controlled ovarian hyperstimulation (COH) in invitro 

fertilisation (IVF) (Review) 

Shanbhag S, Aucott L, Bhattacharya S, Hamilton MA, McTavish AR 

The Cochrane Library 2007, Issue 3

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FASOULIOTIS, ALEX SIMON, and NERI LAUFER 

2000 

•Ovulation induction protocols 

–Cc-hmg 

–High dose FSH / HMG 

–GnRH agonists 

–Minidose GnRHa 

–GH supplementation 

–Glucocorticoids 

–Oral contraceptives 

–Natural cycle 

• Blastocyst transfer 

• Assisted hatching 

• Co-culture 

• IVM

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B.C.Tarlatzis et al 2003 

Management 

� High doses of gonadotrophins 

� Use of recombinant FSH versus purified urinary FSH 

� Luteal initiation of FSH 

� Flare-up GnRH agonist regimens: short and ultra-short protocols 

� Standard-dose flare-up regimens 

� Reduced-dose GnRH agonist flare-up regimens 

� Luteal initiation of GnRH agonist regimens 

� GnRH antagonist regimens 

� Adjunctive use of GH or GH-releasing factor or pyridostigmine 

� Adjunctive use of glucocorticosteroids (dexamethasone) 

� Adjunctive use of nitric oxide (NO)-donors (L-arginine) 

� Pretreatment with COC or progestogens 

� Routine use of ICSI 

� Natural cycle 

Tarlatzis conclusions 

In conclusion, there is a clear need to standardize the 

defenitions of low ovarian response. Well-designed, 

large-scale,randomized, controlled trials are needed to 

assess the eficacy ofthe different management 

strategies. 

The current results which are available are perhaps 

somewhat disappointing, but this should not be too 

surprising as most poor ovarian response women 

appear to have occult ovarian failure. 

Thus, the exhausted ovarian apparatusis unable to react 

to any stimulation, no matter how powerful this might be. 

The ideal stimulation for poor responders still 

remains a challenge, as the hypothesized diminished 

oocyte cohort and poor oocyte quality cannot be 

reversed within the limits of our present capabilities.

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Cochrane (Jan 2007) conclusion…. 

conclusion 

�� NO CLEAR EVIDENCE TO SUPPORT 

ANY PARTICULAR INTERVENTION 

�� “it it is not possible to recommend any 

intervention to replace the currently used 

conventional long protocol..” protocol.. 

Treatment of low responders by 

ART 

�� Ovarian stimulation protocols 

�� Long agonist 

�� Short agonist 

�� Ultrashort agonjst 

�� Stop 

�� Microdose 

�� Different agonist 

�� Antagonist 

�� Agonist antagonist 

�� FSH vs HMG 

�� LH 

• Clomiphen 

• No analogs only 

gonadotropins 

• GH 

• Natural cycle

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Newer Therapies 

�� Testosterone 

�� Letrozole 

�� Luteal estradiol 

�� AACEP 

�� Recombinant LH 

�� Aspirin 

�� OCP 

�� L-arginine arginine (1999) 

�� Prolactin Supplementation 

�� Natural cycle 

�� CAM – complementary and alternative medicine 

�� Donor oocytes 

Relevent stimulation protocols 

�� Long agonist 

�� Microdose agonist 


�� Agonist - antagonist

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Microdose analog 

�� Oral contraception 

�� Third day of OC cessation start 0.005 mg 

Decapeptyl twice daily 

�� FSH (+ ( HMG) 450 – 750 IU daily from 2 nd 

day of Deca 

Schoolcraft, W et al Fertility Sterility 1997 Microdose + GH 

�� Paired analysis of 32 poor responders,

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Comparison of cycles 

1- LONG PROTOCOL 

ALL CYCLES CANCELLED DUE TO POOR RESPONSE 

(E2 < 100 or fewer than 4 follicles after 5 days GT stimulation) 

2 – EXPERIMENTAL PROTOCOL : 

OCP for 21 days 

GnRH agonist + GH from 3 days after cessation of OCP 

until hCG 

FSH from 3 rd day of GnRH/GH, GnRH/GH, 

until at least two oocytes 

18mm+ 

32 cycles – 28 continued, 4 cancelled 

• 28 cycles 

14 pregnancies !

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Detti et al, Fertility Sterility 2005 microdose 

�� 48 consecutive women, underwent 61 cycles of 

treatment 

�� 5 year period 

�� Age >38 

�� Less than 4 oocytes 

�� Peak E2 < 500 pg/ml 

�� Elevated FSH (>13) 

�� Previously cancelled cycle 

I – Stop protocol 

II – Microdose flare protocol 

III – Short agonist flare 

• No statistically significant findings 

• Trend towards higher implantation, clinical pregnancy and 

delivered pregnancy rate in Microdose group

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Franco, JG Jr et al, Reproductive Biomedicine Online, 2006 

�� Meta-analysis Meta analysis of 6 trials, 

comparing GnRH agonist and 

antagonist treatment for poor 

responders 

�� Antagonist – Multiple low dose 

antagonist (0.25 mg) 

�� Agonist – long protocol – 2 

- microdose flare – 4 

microdose 

�� No difference between GnRH agonist or 

antagonist in terms of cycle cancellation rate, 

number of mature oocytes, or pregnancy rate 

�� In analysis of GnRH agonist microdose flare vs 

antagonist (4 trials) - significantly higher rate of 

oocytes retreived in GnRH-a GnRH a flare cycles 

�� no difference in pregnancy outcomes 

�� More trials needed

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Agonist - antagonist 

Orvieto: Orvieto: 

�� 3 days of Deca 0.1 from 1 st day of period 

�� Maximal FSH dose from day 3 

�� Flexible antagonist 

�� 21 cases, 3 ongoing (%14.3) pregnancies. 

Shaare Zedek protocol 

Deca 0.1 from day 21 to period and stop 

Start maximal FSH dose on day 2 

Antagonist when leading follicle > 13mm 

Natural cycle 

�� Pelnick et al Netherlands Hum Repro 9/2007 

�� 1048 cycles 256 women 

�� Preganancy rate 8% per cycle 20% per ET 

�� After 9 cycles CPR of 44% 

�� Poor responders: 

�� Frequently ovulate on smaller follicles 

�� Lower E2, lower fertilization rate 

�� Our unit 43% pregancy rate < 38

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New therapies - Medical 




�� AACEP 

�� OCP 



�� L-arginine arginine 




Androgen Therapy 

�� Transdermal Testosterone 

�� DHEA 

�� 2 cell, 2 GT theory – androgen substrate 

undergoes aromatization to estrogen 

�� Direct autocrine/paracrine effect in regulation of 

follicular function 

�� Low basal testosterone may predict poor IVF 

outcome (Frattarelli, JL & Peterson, EH. Effect of androgen levels on IVF IVF 

cycles, Fertil Steril 2004, 81, 1713-4) 1713 4)

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Balasch, J et al, Human Reproduction, 2006;21(7), 1884 

�� 25 women, with past 2 treatment cycles cancelled 

due to poor response 

�� Transdermal testosterone treatment for 5 days before 

GT (20mg/kg/day) 

� RESULTS: Twenty patients (80%) showed an 

increase of over fivefold in the number of 

recruited follicles, produced 5.8 oocytes, 

received two or three embryos and achieved a 

clinical pregnancy rate of 30% per OPU. 

� There were 20% cancelled cycles. 

Marked improvement in E2, no of 

follicles, p < 0.005

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Testosterone cycle 

�� Less GT stimulation required 

�� Increased antral follicle count 

�� Increased serum androstenedione and 

IGF-1 IGF 1 in non-cancelled non cancelled vs cancelled 

(refelcting ovarian responsiveness to GT 

stimulation) 

Massin, N et al, Human Reproduction 2006 

�� Supplementation at time of recruitment might increase small antral antral 

follicle count and 

improve follicular sensitivity to FSH 

�� 53 women – 2 IVF cycles - before and after transdermal testosterone/placebo 

(randomized) 

�� Treatment of 1g/day for 15-20 15 20 days before the second stimulation, stimulation, 

during GnRH 

downregulation 

�� Significant increase in plasma testosterone for women treated with with 

testosterone 

compared with placebo 

�� No significant difference in plasma FSH, LH, AMH, inhibin B, estradiol, estradiol, 

Δ4-androstenedione androstenedione or antral follicle count 

� No significant difference in number of follicles, oocytes or embryos, but trend towards 

better outcome

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DHEA supplementation 

Casson et al 2000, Dehydropiandrosterone supplementation augments augments 

ovarian stimulation in 

poor responders : a case series. Human Reproduction. 15(10). 2129 212 

�� First documentation of DHEA supplementation for diminished ovarian ovarian 

reserve in 

women 35-40 35 40 wt decreased ovarian sensitivity to FSH 

�� Prospective case series of 5 women undergoing ovarian stimulation stimulation 

before and 

after DHEAS supplementation (80mg/day for 2 months) 

�� Gonadotropin response almost doubled 

- DHEA and DHEAS concentrations fall progressively wt age 

- DHEA administration results in increased serum IGF-1 IGF 

- DHEA is a steroid prohormone for ovarian follicular sex steroidogenesis 

steroidogenesis 

�� *** Treatment in case and control cycles not identical + poor statistical statistical 

analysis ( see – Weerinf, HGI, Gutknect DR and 

Schats R - Augmentation of ovarian response by dehydroepiandrosterone, Human Human 

Reproduction 2001 16(7) 1537 

Case Report: Barad and Gleicher 

Barad,D & Gleicher n , Increased oocyte production after treatment treatment 

with 

dehydroepiandrosterone, Fertility Sterility 2005 84(3) 756 

�� Case report of 42 year old women, decreased 

ovarian reserve 

�� Undergoing treatment for embryo 

cryopreservation for future aneuploidy screen 

�� self treated with DHEA supplement as well as 

acupuncture 

�� Continual improvement in peak E2, oocytes 

retreived, embryos cryopreserved

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DHEA pre-treatment pre treatment and Ovulation 

Induction for IVF among women with a 

history of decreased ovarian reserve 

Barad, Gleicher 

Retrospective cohort study of women treated 

with DHEA 

�� 25 mg td for 4-48 4 48 weeks 

�� 76 cycles in 45 women, 43 before and 33 after 

treatment 

�� Increased oocyte yield and high quality 

oocytes 

DHEA 

�� ASRM Washington DC 200 cases no 

significant side effects about 30% 

pregnancy rate 

�� Shaare Zedek 40 cases 10 pregnancies 

�� Prospective controlled study about to 

begin with Prof Shulman (IVF Meir)

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LETROZOLE – Aromatase Inhibitor 

�� Low responder – lower expression of FSH in 

granulosa cells 

�� Letrozole – aromatase inhibitor – 

- temporary accumulation of intraovarian 

androgens, 

→ Induces a “PCO PCO-like like” state of high follicular 

and serum LH and androgens 

→ enhanced follicullar recruitment 

- blocks E2 synthesis – decreased negative 

feedback at pituitary level 

Garcia-Velasco, Garcia Velasco, J et al, Fertility Sterility 2005 

�� Prospective pilot sudy of 147 women with past 

IVF failure in at least one cycle 

- 4 or less oocytes OR 

- E2

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�� Higher implantation rate – statistically significant 

�� Higher pregnancy rate – not significant 

�� Increased follicular fluid testosterone and 

androstrenedione in treatment group 

�� Increased substrate for estrogen 

�� Promote early follicular growth and proliferation of 

theca and granulosa cells 

�� Androgens stimulate IGF and IGF-1 IGF 1 receptor gene 

expression, promoting follicular steroidogenesis

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Schoolcraft, WB et al, Fertility Sterility 2007 

�� Prospective controlled trial, 578 poor responders 

�� Assigned in 2:1 ratio to ML or AL protocol 

ML – microdose GnRH agonist flare 

AL – letrozole (day 3-8) 3 8) and GnRH antagonist 

(from lead follicle 14mm) 

microdose 

��No No advantage for letrozole/antagonist letrozole/antagonist 

protocol 

Letrozol and antagonist 

��Increased Increased follicular fluid androgens may have negative effect on oocyte quality

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LH 

Barrenetxea, G, Fertil Steril 2007 

�� Prospective randomized controlled trial, 

84 women 

A – GnRH agonist + rFSH 

B – GnRH agonist + rFSH + rLH 

No clinical or stastically siginificant benefit seen 

Clinical effects of ovulation induction with rFSH supplemented with rLH or low-dose low dose rHCG 

in the midfollicular phase in microdose cycles in poor responders. 

responders 

Fertil Steril. Steril. 

2007 Sep;88(3):665-9. 

Sep;88(3):665 9. Berkkanoglu M, , Isikoglu M, , Aydin D, , Ozgur K. 

Antalya In Vitro Fertilization, Antalya, Turkey 

�� 145 women AFC

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Keltz, M et al, fertility Sterility 2007 

שומ י של ל נויצר 

ת ול ולגב 

�� OCP – used to synchronize folliclar development 

and prevent spontaneous LH surge 

�� May eliminate CL and restore sensitivity to FSH 

in the poor responder 

�� OCP may result in hypothalamic and 

gonadotropic suppression following cessation, 

leading to blunting of the 

flare response to GnRH 

�� 19 poor responders, divided into – 

A – pretreatment wt OCP, then GnRH 

agonist flare protocol 

B – GnRH flare protocol only 

�� Comparison of FSH, LH and P after one 

day of treatment with GnRHa

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�� OCP suppresses pre-GnRH pre GnRH-a a FSH but does not blunt flare effect on 

FSH 

�� OCP blunts LH flare, may reduce early rise in follicular androgens, 

androgens, 

providing optimum environment for follicular growth 

�� Pregnancy rate – OCP pretreatment – 41.7% 

no pretreatment – 28.6% (p – 0.19)

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רובע הדות 

. הבשקהה 

? תולאש שי 

םוכיס 

י תל חש י ורי גל ל ו קו ט ו רפ ףאל חכ ו מ ן ו רתי ן י א 

PR 

-ב 

ב רתויב חיכשה ונה 

microdose agonist 

-ה 

-ב 

ב וא ןורטסוטסט תוקבדמב שומישהש 

הוקת 

שי 

דיתעב ומצע תא חיכוי 

Letrozol 

-ב 

ב וא 

DHEA 

�� 

�� 

��

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Frattarelli, J et al, Fertility sterility 2007 

�� Retrospective cohort study of 1250 poor- 

responder women undergoing IVF 


→ decreased platelet production of PGG 

→ lower level of Thromboxane 

→ vasodilation, increased blood flow in ovarian 

arteries 

→ improved quality of oocytes, higher 

implantation, pregnancy and live-birth live birth rates 

�� Step down protocol 

�� 417 women were treated with 81mg 

aspirin beginning during month prior to IVF 

cycle 

833 underwent standard protocol only

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�� Higher peak estradiol, total days of 

stimulation, total GT dose required and 

number of follicles >14mm on day of hCG 

in group treated with aspirin 

�� No difference in implantation, pregnancy 

or live-birth live birth rates 

�� Increase in antral follicle count may be 

offset by inhibition of prostaglandin and 

decreased implantation rate

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Adjuvant L-arginine L arginine treatment for 

IVF in poor responders 

Battaglia, C et al, Human Reproduction, 1999 

�� Pre-cursor Pre cursor of nitric oxide 

�� Vasodilation → increased blood flow in ovarian arteries 

�� 34 poor responders, divided into : 

I - GnRH-a GnRH a + FSH 

II - GnRH-a GnRH a + FSH + L-arginine L arginine (daily supplementation 

until hCG) 

�� Hormone, US + Doppler 

�� arginine, citrulline, nitrite, nitrate and IGF-1 IGF 

�� 3 pregnancies in L-arginine L arginine group, all early pregnancy 

loss, none in control group 

�� Increased no oocytes 

�� Increased no ET 

�� Lower cancellation rates 

�� Significant Doppler flow improvement in uterine and 

perifollicular arteries – decreased blood flow resistance 

�� Inverse corretlation btwn doppler doppler PI and and estradiol estradiol 

concentration 

�� Significantly higher concentrations of – L-arginine, arginine, L- 

citrulline, nitrite, nitrate and IGF-1 

IGF

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New therapies - Medical 




�� AACEP 



�� OCP 

�� L-arginine arginine 





�� COCHRANE, 2006, 

Shanbhag, S

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Effect of deydroepiandrosterone on oocyte and embryo 

yields, embryo grade and cell number in IVF 

Barad and Gleicher, Human Reproduction, 2006 

�� Case control – paired analysis of 25 women undergoing undergoing 

IVF before and after DHEA 

�� 75 mg tds for 17.6 wks (+/- (+/ 2.13) 

�� Increase in – fertilized oocytes, normal day 3 embryos, 

embryos transferred and average embryo score per 

oocyte, (p value

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RECOMBINANT LH 

LH “window window” – 

�� Absence of LH threshold – E2 insufficient for 

follicular development and endometrial 

proliferation 

�� Excess LH – cessation of normal foliicular 

development, atresia 

�� LH supplementation - controversial 

Traditional Therapy – Ovulation 

induction 

�� clomiphene citrate 

�� gonadotropins (urinary + 

recombinant) 

step-up step up vs step-down step down 

�� hMG 

�� pulsatile GnRH 

(hypothalamic hypogonadotropic amenorrhoea)

30 

Traditional therapy – Stimulation for 

ART 

�� GnRH agonist : 

- prevention of LH surge and premature 

luteinization, 

- enhanced folliculogenesis. 

- higher oocyte retrieval rate 

- long protocol 

- microdose flare 

- stop 

�� GnRH antagonists 

- prevent premture LH surge 

- more physiological than agonists as 

pituitary hormone secretion is suppressed 

within a few hours 

- shorter stimulation period 

- no sex steroid withdrawal symptoms 

- less OHSS

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Traditional therapy for poor 

responder 

�� GnRH Antatgonist 

�� Long GnRH 

�� Microdose GnRH 

agonist “flare flare” 

�� GnRH – stop protocol 

Defining the “Poor Poor Responder” 

Responder 

�� 10-15% 10 15% of women undergoing IVF, related to advanced 

maternal age and diminished ovarian reserve 

�� Advanced maternal age 

�� Premature ovarian failure 

�� Decreased ovarian reserve due to: 

�� Genetics 

�� Surgery 

�� Endometriosis 

�� Radiation 

�� Chemotherapy 

�� affects egg production 

�� affects oocyte quality 

�� Low pregnancy rate irrespective of treatment

32 

�� No advantage for letrozole/antagonist protocol 

�� Increased follicular fluid androgens may have 

negative effect on oocyte quality 

Frattarelli, J et al, Fertility sterility 2007 

�� Retrospective paired study of 60 women, treated with 

traditional protocol and luteal estradiol protocol in 

consecutive cycles 

�� 44 women traditional first, 16 women luteal estradiol first 

�� Same protocol both cycles – microdose flare or GnRH 

antagonist PLUS estradiol 

�� fresh IVF cycles only 

�� Pregnancy outcome rates not indicative as no women 

became pregnant in first cycle 

�� Main outcome measure – number of embryos with >7 

cells on day 3

33 

�� No difference in antral follicle count, days of stimulation, 

number of follicles >14mm or endometrial thickness on 

day of surge, or number of embryos transferred 

�� higher peak estradiol (p

34 

AACEP Protocol 

�� OCP 3 weeks 

�� GnRH agonist, long protocol from day 21, 

overlap wt OCP 5-7 5 7 days, stopped at menses 

�� GnRH antagonist commenced day 2 of menses 

�� Estradiol valerate IM every 3 days for 2 doses 

�� Estrogen suppositories to maintain endometrium 

until at least one follicle > 15mm 

�� Stimulation with FSH, then HMG in step-down step down 

�� Ovulation wt hCG, OPU after 34.5 hrs 

�� Estrogen “priming priming” - of FSH receptors 

- slows premature follicular development 

- promotes granulosa cell FSH receptor 

induction 

�� IM administration to prevent conversion to 

estrone

35 

PREGNANCY RATE ACCORDING 

TO DIAGNOSIS 

Elevated FSH 

Unexplained 

AMA ( > 41) 

Severe Endometriosis 

Decreased Ovarian Reserve 

TOTAL 

num 

14/40 

15/52 

5/26 

2/12 

1/ 7 

37 / 137 

% 

35 

29 

19 

17 

14 

27 % 

�� Younger (

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