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POOR OVARIAN
RESPONSE
By Dr. Manal Kamel Mohamed
Definition
It is the “failure of development of
sufficient numbers of mature follicles to
proceed to oocyte retrieval following a
suitably dosed ovarian stimulation
regime”.
The absolute number of oocyte retrieval used as a cut-off is variable but it is usually between 3 - 5.
Ferraretti et al (2011).
Human Reproduction,
Vol.26, No.7 pp. 1616–
1624, 2011
In order to define the poor response in IVF,at least two of the following three featuresmust be present:
(i) Advanced maternal age or any other riskfactor for POR.
(ii) A previous poor ovarian response (POR).
(iii) An abnormal ovarian reserve test (ORT).
Human Reproduction ; 2011 Jul;26(7):1616-24.
ESHRE consensus on the definition of 'poor response' to
ovarian stimulation for in vitro fertilization: the Bologna
criteria.
1) Elderly patients with an abnormal hormonal profile.
2) Young patients with an altered hormonal profile.
3) Young patients with a normal basal hormonalprofile.
Classification
Poor responders actually represent aheterogeneous group of patients who can bedivided clinically into three main groups.
The Ovarian Changes with Aging
Poor ovarian response
FSH and LH receptor
polymorphisms Androgen secretorycapacity reduced
Decreased numbers of
functional LH receptors
Reduced LH bioactivity
Reduced ovarian
paracrineactivity
Increase homocysteine
concentration in follicular fluid
Decrease oxygen content of follicular
fluid
Decrease mitochondrial
energy production
Increase homocysteine concentration in follicular fluid
The Ovarian Changes with Aging
Poor ovarian response
FSH and LH receptor
polymorphisms Androgen secretorycapacity reduced
Decreased numbers of
functional LH receptors
Reduced LH bioactivity
Reduced ovarian
paracrineactivity
Increase homocysteine
concentration in follicular fluid
Decrease oxygen content of follicular
fluid
Decrease mitochondrial
energy production
Decrease oxygen content of follicular fluid
3D power Doppler shows
compartments of
follicular fluid and
perifollicular vessels
Color flow Doppler of
perifollicular vascularity
around a preovulatory follicle
Power flow Doppler image
of a mature follicle
Atretic follicle of preovulatory
diameter
A) Grade A oocytes could support donor nuclei to
develop into a blastocyst with high efficiency.
B) Grade B oocytes could support donor nuclei to
develop into a blastocyst, but with low efficiency.
C) Grade C oocytes could not support donor nuclei to
develop beyond the morula stage, but could be
fertilized by IVF and could then develop further.
D) Grade D oocytes could support neither donor
nuclei nor sperm.
The Ovarian Changes with Aging
Poor ovarian response
FSH and LH receptor
polymorphisms Androgen secretorycapacity reduced
Decreased numbers of
functional LH receptors
Reduced LH bioactivity
Reduced ovarian
paracrineactivity
Increase homocysteine
concentration in follicular fluid
Decrease oxygen content of follicular
fluid
Decrease mitochondrial
energy production
Decrease mitochondrial energy production
The Ovarian Changes with Aging
Poor ovarian response
FSH and LH receptor
polymorphisms Androgen secretorycapacity reduced
Decreased numbers of
functional LH receptors
Reduced LH bioactivity
Reduced ovarian
paracrineactivity
Increase homocysteine
concentration in follicular fluid
Decrease oxygen content of follicular
fluid
Decrease mitochondrial
energy production
FSH and LH receptor polymorphisms
The Ovarian Changes with Aging
Poor ovarian response
FSH and LH receptor
polymorphisms Androgen secretorycapacity reduced
Decreased numbers of
functional LH receptors
Reduced LH bioactivity
Reduced ovarian
paracrineactivity
Increase homocysteine
concentration in follicular fluid
Decrease oxygen content of follicular
fluid
Decrease mitochondrial
energy production
What is importance of Androgen in the follicular growth?
The Ovarian Changes with Aging
Poor ovarian response
FSH and LH receptor
polymorphisms Androgen secretorycapacity reduced
Decreased numbers of
functional LH receptors
Reduced LH bioactivity
Reduced ovarian
paracrineactivity
Increase homocysteine
concentration in follicular fluid
Decrease oxygen content of follicular
fluid
Decrease mitochondrial
energy production
Decreased numbers of functional LH receptors&
Reduced LH bioactivity
The Ovarian Changes with Aging
Poor ovarian response
FSH and LH receptor
polymorphisms Androgen secretorycapacity reduced
Decreased numbers of
functional LH receptors
Reduced LH bioactivity
Reduced ovarian
paracrineactivity
Increase homocysteine
concentration in follicular fluid
Decrease oxygen content of follicular
fluid
Decrease mitochondrial
energy production
Reduced ovarian paracrine activity
Paracrine connectivity in ovarian follicles.
Hillier S G Mol. Hum. Reprod. 2009;15:843-850
© The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Ovarian Reserve Tests
Biological
Chronological Age
Biochemical
Static
- FSH
- FSH : LH
- E2
- AMH
Dynamic
CCCT
Biophysical
Ultrasound
- Antral follicle count
- Ovarian volume
- Ovarian blood flow
Histological
Ovarian Biopsy
Day 3 FSH level FSH interpretation
<10 Normal FSH level. Expect a good response to ovarian
stimulation.
10 - 12 Borderline FSH. Response to stimulation is reduced.
13- 15 Elevated FSH. Reduced ovarian reserve. Reduced response
to stimulation.
16 - 20 Markedly elevated FSH. Marked reduction in response to stimulation
> 20 Very poor (or no) response to stimulation.
2) The level of FSH (follicle stimulating hormone) in theblood - the basal (day 3) FSH level.
Investigations
1) The patient gives a history of responding poorly tomedications used for superovulation in the past.
3) It's also useful to check FSH:LH ratio.
4) It's also a good idea to test estradiol (E2)level on Day 3 at the time check FSH level.
A high E2 level can artificially suppress the FSH back tonormal, thus giving a false sense of security. However, a highE2 level suggests poor ovarian reserve.
5) Other useful indicator of a poor responder isthe low peak oestrogen levels on the day ofoptimal oocyte maturity.
AMH Level
(ng/ml)
Interpretation Expected Response
to FSH
Anticipated Cancellation
Rate with IVF
Anticipated
Pregnancy Rate
with IVF
>3.0 High, often
PCOS
Very High Low Normal
1.0-3.0 Normal Good Low Normal
0.4-0.9 Low Reduced Increased Reduced
<0.4 Very Low Very Poor Very High Very Low
6) Measurement of the Anti-mullarian hormone(AMH) level in the blood is an another test.
Selectively inhibits FSH (TGF-β family) Levels > 45pg/ml poor response to FSHHigh false positive rate Not currently useful
7) Inhibin β:
8) The biophysical tests use ultrasoundtechnology to image the ovaries and thefollicles.
Antral Follicle
CountInterpretation
Expected
Response to FSH
Anticipated
Cancellation
with IVF
Anticipated
Pregnancy
Rate with
IVF
<4 Very low Very poor Very high Very low
4-6 Low Poor High Low
7-10 Reduced Reduced Increased Decreased
11-30 Normal Good Low Excellent
>30Above
Normal(PCOS)
Increased risk of
OHSSLow Good
9) Also, ovarian stromal blood flow is useful in the prediction of ovarian response during IVF treatment
10) A test that can provide earlier evidence of decliningovarian function is the clomiphene citrate challenge test(CCCT).
This is similar to a "stress test" of the ovary;
Measuring a basal Day 3 FSH and estradiol level.
Administering 100 mg of clomiphene citrate from Day 5 to Day 9.
Measuring Day 10 FSH and estradiol level.
Elevated levels of FSH on either Day 3 or Day10 of the cycle suggests thatovarian reserve is poor.
If the sum of the FSH levels is more than 25, then this suggests poor ovarianfunction.
Menses HCG
1 2 3
GnRHa
HMG
a. Short Agonist Protocol
Treatment
1) CYCLE PROTOCOLS: Several stimulation protocols have been suggested to
improve outcome in poor responding patients.
b. Microdose Protocol.
Menses HCG
1 2 3 4
GnRHa 0.2 IU GnRHa 0.1 IU
HMG
c. Ultra-short Protocol
Menses HCG
GnRHa
HMG
1 2 3
d. Antagonist Protocol.
Menses HCG
1 2 3 4 5 6
HMG
GnRH antagonist
e. Soft Protocol.
2) LH supplementation during ovarian stimulation:
Why is LH beneficial in aged women and poor
responders?
Anti-apoptotic effect on granulosa cells
Increase FSH receptor
responsiveness
Up-regulate growth factorsAct synergistically with
IGF-1
Stimulate theca cells for androgen production
aromatized to estrogens
LH supplementation
Product to use for LH supplementation:
a. hMG/HP-hMGb. rec-hLH
EXCEPT
Sharing the same α subunit and 81% of the aminoacidresidues of the β subunit, LH and hCG bind to the samereceptor
Carboxyl terminal segment of β subunit in hMG islonger Higher receptors affinity Longer halflife.
LH and hCG downstream cascade pathways are different:
1) LHR and FSHR expression
2) Meiosis and follicular maturation
3) Follicular development
4) Cellular growth
5) Ovarian stereodogenesis
INCREASE by LH than hCG
1) Aromatase inhibition
2) Apoptosis enhancement
INCREASE
by hCG than LH
Menon KM et al. Biol Reprod 2004; Ruvolo et al. Fertil Steril 2007Grondal ML et al. Fertil Steril 2009;
3) Adjuvant treatments:
Several medications taken prior to or during a cyclehave been suggested to improve outcome in poorresponders.
a. Anti-Oestrogens:
- Clomiphene citrate
- Aromatase Inhibitors” such as Letrozole
b. DHEA:
Decline of DHEA with aging
DHEA
Increases AMH Levels
Increases FSH
receptors
Increase ovarian
steriodogensis
Prevents Granulosacells apoptosis
Increases Ovarian Reserve
Increase recruitable oocyte pool
How DHEA acts?
Increases Pregnancy
RatesHum Reprod
2011;26(7):1905-9
Reprod Biomed Online.2009 Oct;19(4):508-13.
c. Growth Hormone (GH):
Action:1) Stimulates ovarian steroidogenesis.
2) Stimulates follicular development.
3) Enhances the ovarian response to FSH.
mediated via the IGF-1 that actsin synergy with FSH, amplifying itseffects on granulose cells.
d. Dexamethasone:
Dexamethasone
follicular development
&
oocyte maturation
Directly via its isoform (11βHSD) in the granulosa cells
Idirectly, by increasing serum
GH
Increase intrafollicularIGF-1
Immunosuppressionwithin the endometrial
microenvironment
Keay SD, et. al.,
Human Reprod
2001;16: 1861-5.
Melatonin, secreted bypineal gland, is taken upinto the follicular fluidfrom the blood.
Reactive oxygen species(ROS) produced within thefollicles, especially duringovulation process, arescavenged by melatonin
As oxidizing agents can lessen oocyte quality, so melatonintreatment can improves oocyte quality, leading to a higherfertilization rate.
e. Melatonin:
f. L-Arginine
Oral L-arginine supplementation is converted to
nitric oxide which act as vasodilator improve
vascularization in both perifollicular and uterine
arteries improve ovarian response,
endometrial receptivity and pregnancy rate in
poor responder patients .
Weiner et al., 1993;Balakier and Stronell, 1994; Bassil et al., 1997
g. Folic Acid
Supplementation of folic acid diminish a
concentration of homocysteine in both follicular
fluid and serum Oocytes with better quality and
higher degree of maturity.
4) Alternative Medicine:
1.Yoga, to improve pelvic blood flow.
2.Acupuncture, to improve ovarianblood supply.
The future plan:
3D power Doppler need further researchto know if it can diagnose poor responderearly.
Growth hormone as an adjuvant therapyalso need further research to bestandardized usage.
Gene therapy is the future especially foryoung group with FSH R polymorphism.
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