Poor Responders_frank Quinn

Dr Frank Quinn Clinical Director IVF Australia

Definition Intrinsic to the success of IVF is recruiting eggs ‘poor response’ is the failure to recruit adequate

eggs Three or fewer follicles Estradiol < 500pg/ml at time of hCG trigger

Incidence

Etiology Advanced age Ovarian surgery Pelvic adhesions High body mass index 

Reflecting early ovarian aging

Clinical significance Poor pregnancy rates Emotional stress from higher cancellation rate Financial burden from different interventions and

multiple cycles Often donated oocytes becomes the only option

Pregnancy rate in poor responders

Poor responders Interventions Modifying stimulation protocols  Adjuvant therapy 

Modifying stimulation protocols Short vs. long GnRH agonist protocol GnRH agonist short/long vs. GnRH antagonist

protocols Clomiphene citrate with rFSH in flexible GnRH antagonist vs. long GnRH agonist Stop vs. non-stop long GnRH agonist protocol Short GnRH agonist vs. natural rFSH vs. urinary FSH

Adjuvant therapy  Letrozole  Pretreatment

with COCP

 L-arginine  Aspirin  Recombinant

LH  Human growth hormone

Short vs. long GnRH agonist 2 RCT’s Weissman 2003 and Dirnfeld 1991 Weissman Short –

pretreatment with COCP  500ug/d for 4 days then 100ug/d 

Long – pretreatment with medroxyprogesterone 

100ug/d until down regulation then 50ug/d

N=60 hMG and FSH

Short vs. long GnRH agonist

GnRH antagonist vs. long GnRH agonist

GnRH antagonist vs. long GnRH agonist

GnRH antagonist vs. long GnRH agonist

GnRH antagonist vs. short GnRH agonist Malmusi 205 N=152 Short GnRH agonist

Decapeptyl 0.1mg day 1 of cycle  rFSH 450iu daily start day 2 for 6 days, then ?600iu/d 

Antagonist

rFSH 450daily from day 2 for 6 days, then ? 600iu/d  Orgalutran 0.25mg/d when lead follicle >14mm 

GnRH antagonist vs. short GnRH agonist

GnRH antagonist vs. short GnRH agonist No difference in pregnancy rate Antagonist 21.4% Short GnRH agonist 25%

GnRH antagonists may be associated with - simpler stimulation protocols, - lower gonadotropin requirements, - reduced patient costs, - shorter downtimes between consecutive cycles. Greatest advantage of GnRH antagonists is the ability to assess ovarian reserves immediately prior to starting gonadotropin stimulation. The ability to respond to cycle-to-cycle variation in antral follicle counts may allow the optimization of oocyte yield and reduce cycle cancellation rates.

Long GnRH agonist vs. 'stop'protocol

Meta-analysis n=74 each arm Dirnfeld 1991 Garcia-Velasco 2000 More FSH in long protocol  But higher starting dose in Garcia-Velasco More oocytes in ‘stop’ protocol  Not

when random effects model was used

Lower cancellation in long protocol

Long GnRH agonist vs.”stop”

Natural cycle vs. low dose GnRHa flare protocol single embryo ?better quality and ?more receptive endometrium

Morgia 2004 N=70 low dose arm and n=59 in natural cycle No difference in cancellation or miscarriage rate

Natural cycle vs. low dose GnRHa flare protocol

Natural cycle vs. low dose GnRHa flare protocol

CONCLUSION Modifying stimulation protocols No proven effect that one particular stimulation

protocol is better than another in the treatment of poor responders

Adjuvant therapy Addition of Letrozole Aromatase inhibitor, blocks estrogen synthesis with

a resulting decrease in negative feedback at the pituitary ? resulting increase endogenous gonadotropin may enhance ovarian response.

Addition of Letrozole Schoolcraft et al GnRH antagonist and letrozole 2.5mg daily

Goswami et al Long GnRH agonist protocol n=38 No difference in FSH dose, oocytes retrieved or

pregnancy rate (23.1% vs. 24.0%)

Letrozole and poor responders

Letrozole and poor responders

Addition of pyridostigmine

Addition of pyridostigmine

Addition of L-arginine

Addition of L-arginine

Addition of testosterone

Addition of aspirin

Addition of aspirin

Addition of aspirin No difference in live birth rate placebo149/883 (17.9%) vs. aspirin 72/417 (17.3%)

Addition of GHRF GHRH exerts a direct effect on ovarian tissue Enhancing gonadotropin steroidogenesis Formation of cAMP

One study by Howles 1999, did not appear to be

beneficial

Addition of growth hormone GH may increase intra-ovarian IGF-1 IGF-1 augments aromatase activity,  17 beta estradiol,  progesterone production and  LH receptor formation 

IGF-1 also stimulates follicular development.

Addition of human growth hormone 5 RCT’s Berg et al, Fertil Steril 1994;62:113-20.  Dor et al, Hum Reprod 1995;10:40-3.  Suikkari et al, Fertil Steril 1996;65:800-5.  Owen et al. Fertil Steril 1991;56:1104-10.  Zhuang et al. Chin J Obstet Gynecol 510;29:471-4. 

N=138 Poor response At least 2 failed IVF cycles with <5 eggs  E2 <500pg/mL on day hCG and <3eggs prev. cycle  < 2 eggs or >48 amps hMG in 2 cycles  <6 eggs and < 4 embryos on a prev cycle 

Addition of human growth hormone No difference in no. eggs retrieved duration of ovarian stimulation Owen’s study showed reduction in total FSH

Difference in live birth rate (95% CI close to unity, ?clinical

significance may be small)

Addition of human growth hormone

Addition of human growth hormone More studies to address When to start hGH  mid luteal phase through to mid follicular The optimal dosage 

4iu, 8iu, or 12iu/day

Conclusions Poor responders have a significantly lower

pregnancy rate compared to normal responders Many studies are under powered Most interventions have been proven not to be beneficial Different protocols for ovarian stimulation  Addition of treatment therapies 

Addition of human growth hormone demonstrates

promising results with higher live birth rates.