AMH OVARIAN RESERVEMARKER Dr Jyoti Bhasker ,Dr. Sharda Jain Dr. Jyoti Agarwal ,

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AMH

OVARIAN RESERVEMARKER

DR. JYOTI BHASKARDR. SHARDA JAIN

DR. JYOTI AGARWAL

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AGE WISE INFERTILITY

20-25 2.8% infertile

30-34 10% infertile

35-39 33% infertile

40-45 86% infertile

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AGE - DECLINE OF OOCYTES

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MISCARRIAGE RATE

Age 30: 7-15%

Age 31-34: 17-21%

Age 35-39: 17-28%

Age 40: 40-52%

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ANEUPLOIDY

10% of eggs are aneuploidic in young women

30% at the age of 40

50 % at the age of 43

Nearly all the eggs are aneuploidic at the age of 45

6(teVelde and Pearson 2002)

OVARIAN RESERVE

Age is an important independent determinant of fertitlity and miscarriage

But due to considerable individual variation in the age of menopause and age of subfertility.

Chronological age ALONE is a POOR indicator of reproductive aging, and thus of the ovarian reserve.

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OFFER -- OVARIAN RESERVE TEST Infertile womenInfertile women

Over 30 years of ageOver 30 years of agewith a history of with a history of exposure to a confirmed exposure to a confirmed

gonadotoxin gonadotoxin i.e., tobacco smoke, i.e., tobacco smoke, chemotherapy, radiation therapy.chemotherapy, radiation therapy.with a strong family history of early with a strong family history of early menopause ormenopause or

premature ovarian failure.premature ovarian failure.women who have had extensive ovarian women who have had extensive ovarian surgery, i.e., cystectomy and unilateral surgery, i.e., cystectomy and unilateral oophorectomyoophorectomy

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BENEFITS OF ORT IN SUBFERTILE COUPLE

ORT guides in prognosticating ORT guides in prognosticating outcome inoutcome in

individual cases byindividual cases by

Pre-treatment counsellingPre-treatment counsellingChoice of infertility treatmentChoice of infertility treatmentAvoidance of ovarian Avoidance of ovarian hyperstimulationhyperstimulation

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Ovarian ReserveOvarian Reserve

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TESTING FOR OVARIAN RESERVE

Hormone analysis

Ultrasound techniques

Dynamic testing

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HORMONE ANALYSISFollicle Stimulating Hormone (FSH)

Oestradiol

Progesterone

Inhibin B

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FOLLICLE STIMULATING HORMONE

Usually measured Day 2 or 3 of cycle

Women with > 10 IU/l poor response to ART

Women aged more than 30 with one value

of FSH > 14 IU/l do worse on IVF

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DISADVANTAGE

Variation from month to month

Lab wise variation in values due to

different techniques.

Spurious fall after hormone therapy.

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SERUM OESTRADIOL

E2 alone of little value to asses ovarian

reserve

Combined E2 and FSH levels – better than E2 alone.

E2 of > 80 pg/ml day 3 pre IVF cycle- higher cancellation rate

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PROGESTERONE

Doesn’t have any independent role in assessment of ovarian reserve

Early LH surge and elevation of P4 suggested sign of poor ovarian reserve

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INHIBIN B

Hetero dimeric protein similar to AMH

Levels >45 pg/ml – poor response to induction

High false positive rate

Not widely used nowadays.

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CLOMIPHENE CHALLENGE TESTBaseline FSH, LH & E2 followed by CC 100mg/day

from Days 5 to 9

Measure E2, FSH and LH on Day 9 to 11

Exaggerated FSH after CC bad prognostic sign

Along with other tests like FSH or GNRH agonist stimulation test no better inference than basal

values

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ANTRAL FOLLICULAR COUNT

Count of total follicles measuring 2 to 5mm in both ovaries on Day 2/3 of periods.

Can be done in any day of the cycle

To be done by Trans Vaginal Ultrasound

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ANTRAL FOLLICULAR COUNT

NORMAL AFC COUNT – 10-18

POOR RESPONDER - < 7

HYPERRESPONDER - > 20

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DRAWBACKS OF AFCDRAWBACKS OF AFC

Accurate assessment of AFC requires an Accurate assessment of AFC requires an experienced sonographerexperienced sonographer and can be limited in and can be limited in patients who have had pelvic surgery or patients who have had pelvic surgery or

uterine uterine fibroids and in those who are obesefibroids and in those who are obese

Moderate interobserver and intercycle Moderate interobserver and intercycle variabilityvariability of of

AFC determinations limits its reproducibility. AFC determinations limits its reproducibility.

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FACTORS AFFECTING AFCFACTORS AFFECTING AFC

Oral contraceptive use (decreases)Oral contraceptive use (decreases)

Polycystic ovary syndrome (PCOS) Polycystic ovary syndrome (PCOS) (increases).(increases).

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AFC

So far, assessment of antral follicle count by

ultrasonography, best predicts the quantitative aspect of

ovarian reserve.

Most cost effective SINGLE predictor of

ovarian reserve -- IS AFC

(Scheffer, et al., 2003)

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ANTI-MULLERIAN HORMONE

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AMHAMH is a glycoprotein

Originally known as Mullerian Inhibiting Substance(MIS)

Appears in females at puberty

Produced by granulosa cells of pre-antral and small antral follicles of 4-6 mm

AMH is not expressed in atretic follicles and theca cells.

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AMH is produced by the small growing (primary and AMH is produced by the small growing (primary and preantral) follicles in the postnatal ovary and has two preantral) follicles in the postnatal ovary and has two sites of action. It inhibits initial sites of action. It inhibits initial follicle recruitment (1) and inhibits FSH-dependent follicle recruitment (1) and inhibits FSH-dependent growth and selection of preantral and small antral growth and selection of preantral and small antral follicles (2).follicles (2).

Model of AMH action in the ovary.Model of AMH action in the ovary.

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The intrafollicular concentrations of AMH in normal human antral follicles show a gradual reduction as the diameter of the follicle increases, and a sharp decline is observed around 8mm

Physiological function- prevent excessive follicle recruitment. Acts as a Gatekeeper

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AMH - unaffected

Not cycle dependant-can be measured any day

Less cycle to cycle variation than FSH.Not altered after down regulation with

GNRH agonist.Pregnancy

AMH – factors that Increase Polycystic ovaries

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AMH – factors that decrease

Increasing age Increasing age Race and EthinictyRace and Ethinicty Obesity Obesity Smoking, Alcohol IntakeSmoking, Alcohol Intake Administration of Gonadotropins Administration of Gonadotropins Administration of chemotherapy or Administration of chemotherapy or radiation radiation Surgical removal of one or both ovaries Surgical removal of one or both ovaries Contraceptive PillsContraceptive Pills

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AMH BLOOD LEVEL

High (often PCOS) Over 3.5 ng/ml

Normal Over 1.4 ng/ml

Low Normal Range 0.7 – 1.3 ng/ml

Low 0.3 - 0.6 ng/ml

Very Low Less than 0.3 ng/ml

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AMH – NORMAL RANGE

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AMH BLOOD LEVEL

AMH of less than 1.36 ng/ml has a sensitivity of 75.5% and specificity of 74.8% in prediction of poor response.

AMH > 3.5 ng/ml has a sensitivity of 88% and

67% specificity in prediction of hyperstimulation

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WE DO HAVE EXCEPTIONS IN REALITY !!!

42 YRS OLD LADY, WITH AMH OF 0.5 , SPONTANOUS CONCEPTION--- NOW 28 WEEKS. NO MISCARRIAGE, NO ANEUPLOIDY

THESE CUTOFFS ARE GUIDELINES WHICH HELP IN:1. COUNSELLING

2. SELECTING THE OPTIMAL PROTOCOL.DECISION HAS TO BE COLLECTIVE –

WOMAN’S CHOICE GETS THE PRIORITY

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Understanding AMH measurement methods

AMH is measurable in serum

TWO METHODS AVAILABLE ARE Diagnostic system Lab ( DSL) (ng/ml) Immunotech Beckman Coulter ( IBL) assay.

( pmol/l)

NEW METHOD : AMH Generation II assay

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AMH

Increasing age means a decreasing AMH level

Lower AMH levels at any given time irrespective of age predicts a poor

response to ART.

High AMH levels – candidates prone for OHSS.

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ADVANTAGE OVER OTHER ORT MARKERS

It is the earliest marker to change with ageIt shows the least intercycle and intracycle

variabilityIt can be randomly measured during the cycleIt shows no modifications during GnRHaIt needs no modification in hypothalamic

amenorrheaIt is both more convenient and informative

than basal FSH

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INDIVIDUALISED AMH TAILORED COH

Improves embryo transfer rates, the incidence of fertilization, pregnancy and live birth rates.

Reduces incidence of adverse outcomes,

such as OHSS and failed fertilization

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PROPOSED AMH BASED PROTOCOLS

Low AMH (< 1.4 ng/ml) Cycle cancellation or poor response a. Inform the patient about the cycle

cancellation or no transfer b. Low possibility of pregnancy c. Avoid long suppression d. Antagonist cycle e. Use of HMG for stimulation Normal AMH (1.4-3.5 ) Normal

Response a. Standard protocol

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PROPOSED AMH BASED PROTOCOLS

HIGH AMH (> 3.5 ng/ml) a. Inform about the risk of OHSSb. Avoid depot GnRHac. Low FSH dosed. Antagonist cycle preferrede. Agonist Triggerf. Blastocyst transfer or Freeze all

embryos and transfer later.

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CONCLUSION Anti mullerian hormone (AMH) alone

or best in combination with antral follicular count (AFC)

is the BETTER INDICATOR

of ovarian reserve than any other hormonal or

sonographic markers available at present.

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