Women are very different to men with regard toreproductive ageing.

A woman’s entire lifetime’s supply of eggs ispresent at birth.

Decreasing ovarian reserve is inevitable withincreasing age, resulting in complete infertility byage 40-50.

Decreasing ovarian reserve has a significantnegative effect on a couple’s reproductiveprospects from age 37 onwards but earlier forsome women.

Ovarian reserve is a measure of how well theovaries are still functioning at a certain point intime.

Ovarian reserve is a term used todescribe the functional potential of theovary and reflects the number andquality of oocytes within it.

A good test of ovarian reserve should bepredictive of conception (with orwithout treatment) and should indicatehow long current levels of ovarianactivity can be maintained beforeovarian ageing sets in.

Ovarian reserve is a complex clinical

phenomenon that is influenced by age,

genetics, environmental variable.

Testing is indicated in :

• women over 30 years of age

• women with a history of exposure to a confirmed

gonadotoxin, i.e., tobacco smoke,

chemotherapy, radiation therapy.

• women with a strong family history of early

menopause or premature ovarian failure.

• women who have had extensive ovarian surgery,

i.e., cystectomy and unilateral oophorectomy.

Markers of ovarian reserve

1 - Age

2 - Basal serum FSH

3 - Basal serum estradiol

4 - Basal LH/FSH ratio

5 - Basal serum inhibin-B level

6 - Basal serum anti-Müllerian hormone level

7 - Basal ovarian volume

8 - Basal antral follicle count

9 - Ovarian stromal blood flow

FSH (Follicle Stimulating Hormone)

- lower is better (Normal <10 iu/L)

› test cycle day 2-4

› fluctuates between cycles when ovarian reserve poor

AMH (Anti Mullerian Hormone)

› higher is better (normal>5pmol/L)

› less fluctuation between cycles

Antral Follicle Count (AFC)

› higher is better

› 5-10 AF’s per ovary –normal reserve

› <3 AF’s per ovary –poor reserve

› >10-15 AF’s per ovary – ‘polycystic’

Menstrual cycle length –

Shortening cycles indicate deterioratingovarian reserve.

Age and fertility:

In many cases, a woman’s age is the

single most important indicator of

fertility potential. A woman’s fertility

starts decreasing in her late twenties,

and decreases further after age 35.

While a 20 year old woman and a 40

year old woman ovulate the

approximate same number of times

each year, their monthly pregnancy

rate, or fecundity, is much different.

FSH FSH is the hormone released by the pituitary

gland in the brain to stimulate the ovaries toproduce a dominant follicle (which contains anegg).

A “good quality” egg releases certainsubstances (e.g. inhibin-B, estrogen) thatsuppress the FSH level (negative feedback).When the egg quality is compromised, thesenegative feedback signals are weak and there isa resultant increase in FSH levels.

Day 3 FSH is an indirect measure of the size ofthe follicle cohort and is regulated by variousfactors, including inhibins, activins, estradiol andfollistatins .

Antral follicle count measurements*A normal ovary should have a volume of at least 3

cc with at least 6 – 15 antral follicles.

*Antral follicles are small, fluid filled cysts that are

normally found in the ovaries. The higher the antral

follicle count, the better the fertility potential.

*Small ovaries may indicate compromised fertility

potential, as there may be less follicles - and

therefore less eggs - available within the ovaries.

*The performance of AFC for predicting failure to

achieve pregnancy is poor. This is because while

AFC determines the number of oocytes, a clinically

relevant outcome (pregnancy or live birth)

depends on oocyte quality as well as quantity.

Serum estradiol

Elevated basal estradiol may predict the poorresponse even when basal FSH is normal.

The value of cycle day 3 estradiol levels in theprediction of ovarian reserve is still debatable.

Inhibin-B

Inhibin-B is mainly produced by the granulosacells in growing follicles and offers a moreimmediate assessment of ovarian activity thanother serum tests.

A fall in day 3 inhibin-B levels may predict poorovarian reserve before the expected rise in day3 FSH.

Factors affecting Inhibin-B measurements:• Obesity (decreases)

• PCOS (increases)

• Exogenous FSH administration (increases)

• Oral contraceptive use (decreases).

Anti-Müllerian hormone Antimüllerian hormone (AMH) also known as

Müllerian Inhibiting Substance (MIS) is a newdiagnostic marker of ovarian function. Theexistence of AMH was first proposed in 1947 byProfessor Alfred Jost.

This hormone is made in the sertoli cells of thetestes of men.

It was thought not to exist in women. In recentyears, it has been found in women starting atpuberty.

age unit value

Younger than 24

months

ng/mL

pmol/l

15 to 500

100 to 3500

24 months to 12 years ng/mL

pmol/l

7 to 240

50 to 1700

More than 12 years ng/mL

pmol/l

0.7 to 20

5 to 140

In men, inadequate embryonal AMH activity can lead to

the Persistent Müllerian duct syndrome (PMDS), in which a

rudimentary uterus is present and testes are usually undescended.

The AMH gene (AMH) or the gene for its receptor (AMH-RII) are

usually abnormal

Anti-Müllerian hormone (AMH) is produced bythe granulosa cells of the recruited follicles untilthey become sensitive to FSH .

AMH has been identified as a regulator of therecruitment, preventing the depletion of allprimordial follicle pool at once.

AMH is a glycoprotein growth factor and amember of the transforming growth factorsuperfamily(TGF-B)with a molecular weight of140kDa.

It is primarily produced by the pool of early-growing follicles, which are believed to serveas a proxy for the number of primordial folliclesin the ovary

AMH is expressed on activation of follicle growth and continues

throughout the pre-antreal stages.AMH expression declines at approximately 4-mm follicle

diameter with little beyond 8 mm; thus, there is a switch from

AMH to oestradiol production at the time when follicleselection occurs.

Age unit value

Younger than 24 months ng/mL

pmol/l

Less than 5

Less than 35

24 months to 12 years ng/mL

pmol/l

Less than 10

Less than 70

13–45 years ng/mL

pmol/l

1 to 10

7 to 70

More than 45 years ng/mL

pmol/l

Less than 1

Less than 7

What is the role of AMH in assessing

ovarian aging and ovarian reserve?

AMH levels decrease over time even in

“fertile” women who have regular

menstrual cycles.

AMH levels correlate well with the ovarian

antral follicle count and were the only levels

that decreased longitudinally over time

compared with FSH, estradiol, and inhibin-B

levels.

With ovarian aging, the first change is a

decrease in AMH levels, followed by a

decline in inhibin-B and finally by an

increase in FSH levels.

AMH levels do not vary significantly duringthe menstrual cycle and can therefore bedrawn on any day of the cycle!

Women who are overweight have 65%lower AMH levels than thin women,indicating that obesity may be associatedwith decreased ovarian reserve and/orwith ovarian dysfunction.

What are the factors that influence AMHlevels?

A. Factors that decrease AMH• Increasing age

• Obesity

• Administration of gonadotropins

• Administration of chemotherapy orradiation

• Surgical removal of one or both ovaries

B. Factors that increase AMH• Polycystic Ovarian Syndrome

C. Factors that do not influence AMH

• Day of menstrual cycle

• GnRH agonists

• Birth Control Pills

• Pregnancy

What are “normal” and “abnormal” levels of

AMH?

• AMH levels less than 0.2 - 0.5 ng/mL are associated

with increased IVF cycle cancellation rates and

fewer eggs retrieved from the ovaries.

• AMH levels greater than 2.5 ng/mL are associated

with greater number of eggs retrieved and a better

fertility potential.

Recent data suggest that AMH levels may reflect

fertility potential more accurately than

conventional markers like FSH, inhibin-B or estradiol

levels.

AMH levels may be better indicators of the ultimate

chance that a woman will achieve a pregnancy

than FSH levels.

A high AMH level (greater than 3.6 ng/mL) may

predict that a woman is at increased risk for

ovarian hyperstimulation syndrome.

› In such women, the dose of medications with IVF can bereduced to avoid this side effect of fertility treatments.

Women with higher AMH values will tend to have

better response to ovarian stimulation for IVF and

have more eggs retrieved. In general, having more

eggs with IVF gives a higher success rate.

AMH levels probably do not tell us much

about egg quality, but having more eggs at the IVF

egg retrieval gives more to work with – so more

likely to have at least one high quality embryo

available for transfer back to the uterus.

Pre- antral and small antral follicles produce AMHx6 the density of pre-antral follicles comparedwith the normal ovary in PCOS. (Webber et al,2003)

High AMH levels in PCOS also due to increasedproduction by individual follicles (Pellatt et al,2007)

Some have suggested that asymptomaticpolycystic morphology (PCOM) is not an entitybut a mild variation of normal.

A excess LH +insulin

Multiple small follicles

AMH

FSH action

Anovulation progesterone