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Ovarian Reserve SOGC, 2011 NICE, 2013 ESHRE, ACOG, 2015 Aboubakr Elnashar Benha university, Egypt ABOUBAKR ELNASHAR

OVARIAN RESERVE

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  • 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

    ABOUBAKR ELNASHAR

  • 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

    ABOUBAKR ELNASHAR

  • ABOUBAKR ELNASHAR

  • At birth: 12 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

    ABOUBAKR ELNASHAR

  • Number of primordial follicles and

    Poor quality of oocytes in relation to

    Female age and

    Reproductive events.

    ABOUBAKR ELNASHAR

  • ABOUBAKR ELNASHAR

  • OVARIAN RESERVE

    What:

    Reproductive potential

    function of the number and quality of remaining

    oocytes.

    ABOUBAKR ELNASHAR

  • 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)

    ABOUBAKR ELNASHAR

  • 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)

    ABOUBAKR ELNASHAR

  • 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.

    ABOUBAKR ELNASHAR

  • 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

    ABOUBAKR ELNASHAR

  • 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

    hypothalamicpituitary 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

  • ABOUBAKR ELNASHAR

  • 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)

    ABOUBAKR ELNASHAR

  • Use a womans 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

    ABOUBAKR ELNASHAR

  • 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

    ABOUBAKR ELNASHAR

  • 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)

    ABOUBAKR ELNASHAR

  • 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)

    ABOUBAKR ELNASHAR

  • 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.

    ABOUBAKR ELNASHAR

  • 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.

    ABOUBAKR ELNASHAR

  • >39 y3438 y2433yParameter

    1.1

    (0.52.3)

    1.6

    (0.82.9)

    2.1

    (1.13.4)

    AMH level

    (ng/mL)Median (interquartile range)

    7.9

    (6.210.6)

    7.4

    (69.4)

    6.9

    (5.58.3)

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

    7

    (411)

    10

    (613)

    11

    (816)

    AFCMedian (interquartile range)

    (Imog et al ,2011) ABOUBAKR ELNASHAR

  • 1. Antral Follicle Count (AFC)

    Total number of follicles measuring 210 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

    ABOUBAKR ELNASHAR

  • Antral follicle count

    ABOUBAKR ELNASHAR

  • AFC

    Standardize: 210 mm, D2-4 for more consistency and practicality

    (Broekmans et al., 2010).

    ABOUBAKR ELNASHAR

  • ABOUBAKR ELNASHAR

  • 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

    ABOUBAKR ELNASHAR

  • 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 58 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

    ABOUBAKR ELNASHAR

    http://molehr.oxfordjournals.org/search?author1=J.V.+Jeppesen&sortspec=date&submit=Submithttp://molehr.oxfordjournals.org/search?author1=J.V.+Jeppesen&sortspec=date&submit=Submithttp://molehr.oxfordjournals.org/search?author1=J.V.+Jeppesen&sortspec=date&submit=Submit

  • ABOUBAKR ELNASHAR

  • ABOUBAKR ELNASHAR

  • SELECTION OF PROTOCOL ACCORDING TO

    OVARIAN Reserve

    Reserve Low Average High

    AFC 14

    AMH 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

    ABOUBAKR ELNASHAR

  • 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

  • ABOUBAKR ELNASHAR

  • 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.

    ABOUBAKR ELNASHAR

  • Thank youABOUBAKR ELNASHAR