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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

 RecombinantLH
 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.