Ovarian

Reserve

SOGC, 2011

NICE, 2013

ESHRE, ACOG, 2015

Aboubakr ElnasharBenha university, Egypt

ABOUBAKR ELNASHAR

CONTENTS

1.OVARIAN AGING

2.OVARIAN RESERVE

3.OVARIAN RESERVE TESTS

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OVARIAN AGINGWhat:

Oocytes peak in number during fetal life.

Over time, oocytes decrease in quantity and

quality and do not regenerate

Although this reproductive decline occurs with age,

there is significant variation in fertility among women

of similar age, which highlights the unpredictability

and individuality of the reproductive aging process

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At birth: 1–2 million oocytes in her ovaries

As a woman ages:absolute number of developing follicles declines at a

rate that is bi-exponential to her age.

At 37.5 y:Rate of follicle loss (atresia) more than doubles

OR falls below the critical level of 25,000

As the ovarian follicular pool decreases: Infertility

Cycle shortening

Cycle irregularity and finally

Menopause

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Number of primordial follicles and

Poor quality of oocytes in relation to

Female age and

Reproductive events.

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OVARIAN RESERVE

What:

Reproductive potential

function of the number and quality of remaining

oocytes.

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Predictors of ovarian reserve

1. Age

2. History of poor response or cancelled cycles

3. Menstrual cycle length

4. ORT:

Most important: AFC &AMH

best test for quantitative OR

(Broer et al., 2009; IMPORT study 2013)

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Decreased or diminished ovarian reserve (DOR)

What:

Commonly have regular menses but

reduced quantity of ovarian follicles:

limited response to ovarian stimulation

reduced fecundity

(probability of achieving a live birth in a single

reproductive cycle).

Distinct from:

menopause or

premature ovarian failure (also referred to as

primary ovarian insufficiency)

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Causes:

In most cases, are unknown.

It is unclear whether DOR represents a pathologic condition resulting from

1. abnormally rapid atresia in a normal pool of oocytes,

2. normal atresia of an abnormally small initial pool of oocytes, or

3. simply the extreme end of a normal bell-shaped population distribution of the number of oocytes at a given age.

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Risk Factors

• Advanced reproductive age (older than 35 years)

• Family history of early menopause

• Genetic conditions:

45,X mosaicism

• FMR1 (Fragile X) premutation carrier

• Conditions that can cause ovarian injury endometriosis

pelvic infection

• Previous ovarian surgery (eg, for endometriomas)

• Oophorectomy

• History of

gonadotoxic therapy or

pelvic irradiation

• SmokingABOUBAKR ELNASHAR

OVARIAN RESERVE TESTS:

The purpose

Predict ovarian reserve and/or reproductive potentialIdentify infertility patients at risk for DOR, who

are more likely to

exhibit a ‘‘poor’’ response to gonadotropin

stimulation

have a lesser chance of achieving pregnancy

with ART.

Prognosis

Dose of the drugs

Safety considerationABOUBAKR ELNASHAR

Indications:

≥ 35 ys not conceived after 6 months or

< 35 ysEndometriosis

Unexplained infertility

Single ovary

Previous ovarian surgery,

Poor response to FSH,

Previous exposure to chemotherapy or

radiation (Iii-b) SOGC, 2011

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Types:

Biochemical tests

reflect the biology of the aging ovary, the one component of the reproductive system most closely related to decreased fecundity.Basal measurements

FSH, AMH, E2, inhibin B

Dynamic= Provocative tests

assess the response of the

hypothalamic–pituitary– ovarian axis to

a stimulus.

CCCT.

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Ultrasonographic

AFC

ovarian volume.

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The ideal screening test

Purpose of a screening test is to identify persons

at risk for a disease.

Reproducible:

with low intercycle and intracycle variability

High specificity

to minimize the risk of a false-positive

determination of DOR in a woman with

normal ovarian reserve

Specificity

Probability of the test to be negative when the disease is absent

True negative test ABOUBAKR ELNASHAR

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Selection of tests

AMH, AFC and FSH individually predict low and high

response, and combinations did not have any better

predictive accuracy criteria, no merit in

recommending them in combination.

The choice should be based

laboratory resources

availability of a skilled ultrasonographer.

Do not use any of the following tests

ovarian volume

ovarian blood flow

inhibin B

E2 as individual tests

CCCT.(NICE, 2013) ABOUBAKR ELNASHAR

The most appropriate ORT to use in practice are

basal FSH plus E2 levels or

AMH levels.

AFC, also may be useful if there is an indication

to perform TVS(ESHRE, ACOG, 2015)

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Use a woman’s age

as an initial predictor of her overall chance of

success through natural conception or with IVF

Use one of the following

High responseLow response

16 or more4 or lessTotal AFC

3.5 or more

25

0.8 or less

5.5

AMH

ng/ml

pmol/l

Conversion ratio:7

4 or less8.9 or moreFSH IU/L

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Significance:

1. All detect the quantity rather than the quality of the

follicular pool

2. Although these tests are used to assess oocyte

quantity and quality, the best surrogate marker for

oocyte quality is age(Broekmans et al. 2006)

3. Add prognostic information to the counseling and

planning process:

help couples choose among treatment options

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4. Predict response to ovarian stimulation and

potentially, successful outcome with ART.

5. Help in determining

dose of HMG/FSH

protocol of stimulation to be used

but they are poor predictors of PR (Fauser et al 2007)

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6. Poor predictive value for non pregnancy:

should be used to exclude women from tt only

if levels are significantly abnormal. (II-2a) SOGC, 2011

should not be the sole criteria used to deny

patients access to ART or other treatments.

{Evidence of DOR does not necessarily equate

with inability to conceive}.(ACOG, ESHRE, 2015)

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Female age and ovarian reserve test

useful for discussing prognosis and recommending a

treatment plan.

Younger women with DOR:

reduced oocyte numbers but

may have normal oocyte quality

older women with normal OR:

may have a good number of oocytes but

an age-appropriate decrease in oocyte quality.

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When test results suggest DOR:

Infertility evaluation

Counsel the woman

opportunity to conceive may be shorter than

anticipated

attempting to conceive sooner rather than later is

encouraged.

Pursue more aggressive treatment options to

achieve pregnancy.

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>39 y34–38 y24–33yParameter

1.1

(0.5–2.3)

1.6

(0.8–2.9)

2.1

(1.1–3.4)

AMH level

(ng/mL)Median (interquartile range)

7.9

(6.2–10.6)

7.4

(6–9.4)

6.9

(5.5–8.3)

FSH level (IU/L)Median (interquartile range)

7

(4–11)

10

(6–13)

11

(8–16)

AFCMedian (interquartile range)

(Imog et al ,2011) ABOUBAKR ELNASHAR

1. Antral Follicle Count (AFC)

Total number of follicles measuring 2–10 millimeters

in diameter that are observed during an early

follicular phase TVS.

Follicles >2mm are sensitive to FSH, termed as

recruitable(Broekmans et al.,2010; La Marca et al.,2011)

Correlates with size of

the remaining follicular pool

number of oocytes retrieved following stimulation.

– Inter-observer variation does not affect the

predictive power of the test.

– Automated 3D measurement of AFC

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Antral follicle count

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AFC

Standardize: 2–10 mm, D2-4 for more consistency and practicality

(Broekmans et al., 2010).

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2. Anti-Mullerian hormone (AMH)

Glycoprotein

Produced by: granulosa cells of pre-antral and small antral

follicles

falls linearly with increasing age

Not cycle dependant: can be measured any day

Less cycle to cycle variation than FSH

Not effected by GnRHa: can be measured during downregulation

Expensive

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AMH gene expression and total AMH protein increased until a follicular diameter of 8 mm, after which a sharp decline occurred. In vivo modelling confirmed that 5–8 mm follicles make the greatest contribution to serum AMH, estimated for the first time in human to be 60% of the circulating concentration. J.V. Jeppesen et al, 2013

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SELECTION OF PROTOCOL ACCORDING TO

OVARIAN Reserve

Reserve ‘Low’ ‘Average’ ‘High’

AFC <7 7-14 >14

AMH <1.1 ng/ml 1.1-3.5 >3.5

Starting FSH

dose IU

Amp

375

5

225

3

150

2

Protocol - Antagonist

-Microdose flare

-Agonist stop

-GH

-Natural

-Modified natural

-Long

protocol

-Antagonist

-Long

protocol

-Antagonist

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3. Follicle Stimulating Hormone (FSH)

– Produced by the pituitary gland to stimulate eggs recruitment

and development

– If there are lots of eggs in the ovary,

– The ovary will send a signal to reduce FSH production

– FSH remains low

– If there are few eggs in the ovary,

– no meaningful signal will be send back and so

– FSH keep rising till it exhibits a response

– Measured Day 2 or 3 of cycle:

• Inconvenience of timing the sample

– Cannot predict hyper response

– Require concomitant oestradiol measurement

• Inter cycle variability from month to month

(Brown et al., J Repro Med 1995)

– Different laboratories different techniques/ levelsABOUBAKR ELNASHAR

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AMH Vs FSH

1. more expensive

2. significantly less inter- and intra-menstrual cycle

variability.

3. can be measured at any point of the menstrual

cycle unlike FSH, which is only interpretable

when measured during the first few days of the

cycle (‘baseline’).

4. During the earlier stages of decreased ovarian

reserve, there are often wide cycle to cycle

fluctuations in FSH level, not seen with AMH.

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Thank youABOUBAKR ELNASHAR