Poor ovarian Response

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



FSH and LH receptor





Reduced ovarian

paracrineactivity




fluid


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.



FSH and LH receptor





Reduced ovarian

paracrineactivity




fluid


energy production

Decrease mitochondrial energy production



FSH and LH receptor





Reduced ovarian

paracrineactivity




fluid


energy production

FSH and LH receptor polymorphisms



FSH and LH receptor





Reduced ovarian

paracrineactivity




fluid


energy production

What is importance of Androgen in the follicular growth?



FSH and LH receptor





Reduced ovarian

paracrineactivity




fluid


energy production

Decreased numbers of functional LH receptors&




FSH and LH receptor





Reduced ovarian

paracrineactivity




fluid


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: [email protected]

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

http://humrep.oxfordjournals.org/content/14/7/1690.full



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.

Health & Medicine

Poor ovarian Response