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Ovarian reserve
and infertility
Dr. Sundus Yousif Kellow
C.A.B.O.G
Definition
• Ovarian reserve is a term used to describe the
functional potential of the ovary and reflects the number
and quality of oocytes within it.
• A good test of ovarian reserve should be predictive of
conception (with or without treatment) and should
indicate how long current levels of ovarian activity can
be maintained before ovarian ageing sets in.
Ovarian Reserve
• Ovarian reserve is a complex clinical phenomenon that is
influenced by age, genetics, environmental variable
• For the general practitioner performing an infertility
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evaluation, we recommend focusing on the following
groups of women for ovarian reserve testing:
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.
In a subfertile population attending for fertility treatment, a
test of ovarian reserve should guide us in
prognosticating outcome in individual cases by
(i) predicting the chances of pregnancy and live birth with
or without treatment and ;
(ii) selecting an optimal dose of ovarian stimulation where
treatment using ovarian stimulation is planned.
Markers of ovarian reserve
A/Static tests
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
B/Dynamic tests
1 - Clomiphene citrate challenge test (CCCT)
2 - GnRH agonist stimulation test (GAST)
3 - Exogenous FSH ovarian reserve test (EFORT)
The ideal ORT that may be usefule clinically has yet to be
ascertained.
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.
Natural Decline of Oocytes with Age
FSH
• FSH is the hormone released by the pituitary gland in
the brain to stimulate the ovaries to produce a dominant
follicle (which contains an egg).
• A “good quality” egg releases certain substances (e.g.
inhibin-B, estrogen) that suppress the FSH level
(negative feedback). When the egg quality is
compromised, these negative feedback signals are weak
and there is a resultant increase in FSH levels.
• Day 3 FSH is an indirect measure of the size of the
follicle cohort and is regulated by various factors,
including inhibins, activins, estradiol and follistatins .
It is important to realize that FSH levels have low
sensitivity, meaning that not everyone with a diminished
ovarian reserve will have an abnormally elevated FSH
level.
Large inter-cycle variations in basal FSH remain a frequent
problem.
An elevated FSH does mean that achieving a successful
pregnancy with any type of fertility treatment, including
with IVF, will be compromised. At the same time, a mild
elevation in the FSH level may be a reason to pursue
infertility treatment more aggressively and proceed
directly to IVF.
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.
5-10 per side
Low A F Count
<6 in total
PCO
Factors affecting AFC measurements:
• Oral contraceptive use (decreases)
• Polycystic ovary syndrome (PCOS) (increases).
Drawbacks of AFC:
• Accurate assessment of AFC requires an experienced
sonographer and can be limited in patients who have
had pelvic surgery or uterine fibroids and in those who
are obese
• Moderate interobserver and intercycle variability of AFC
determinations limits its reproducibility.
• As with basal FSH measurement, the intercycle variability
of AFC does not correlate well with IVF outcome in
individual patients.
Serum estradiol
• Elevated basal estradiol may predict the poor response
even when basal FSH is normal.
The value of cycle day 3 estradiol levels in the prediction of
ovarian reserve is still debatable.
Inhibin-B
• Inhibin-B is mainly produced by the granulosa cells in
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growing follicles and offers a more immediate
assessment of ovarian activity than other serum tests.
A fall in day 3 inhibin-B levels may predict poor ovarian
reserve before the expected rise in day 3 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 new diagnostic marker of
ovarian function. The existence of AMH was first
proposed in 1947 by Professor Alfred Jost. This hormone
is made in the testes of men. It was thought not to exist
in women. In recent years, it has been found in women
starting at puberty.
Anti-Müllerian hormone (AMH) is produced by the
granulosa cells of the recruited follicles until they
become sensitive to FSH . AMH has been identified as a
regulator of the recruitment, preventing the depletion of
all primordial follicle pool at once.
AMH is a glycoprotein growth factor and a member of the
transforming growth factor superfamily(TGF-B)with a
molecular weight of 140kDa. It is primarily produced by
the pool of early-growing follicles, which are believed to
serve as a proxy for the number of primordial follicles in
the ovary
AMH Reproduction.
expression
in mouse ovaries. (A) AMH is expressed in granulosa cells of
2006 Jan;131(1):1-9
primary (P), preantral (PA) and small antral (SA) follicles. (B) AMH expression
disappears in antral (A) and atretic (At) follicles. Expression is lost last in the
granulosa cells surrounding the oocytes. AMH expression was detected using
a monoclonal antibody that recognises rat, mouse and human AMH.
Copyright ©2010 Society for Reproduction and Fertility
Model of AMH action in the ovary. Progressing stages of folliculogenesis
are depicted. AMH is produced by the small growing (primary and
preantral) follicles in the postnatal ovary and has two sites of action. It
inhibits initial follicle recruitment (1) and inhibits FSH-dependent
growth and selection of preantral and small antral follicles (2).
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 during the
menstrual cycle and can therefore be drawn on
any day of the cycle!
• Women who are overweight have 65% lower AMH
levels than thin women, indicating that obesity may be
associated with decreased ovarian reserve and/or with
ovarian dysfunction.
What are the factors that influence AMH levels?
A. Factors that decrease MIS/AMH
• Increasing age
• Obesity
• Administration of gonadotropins
• Administration of chemotherapy or radiation
• Surgical removal of one or both ovaries
B. Factors that increase MIS/AMH
• Polycystic Ovarian Syndrome
C. Factors that do not influence MIS/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 be reduced to avoid this side
effect of fertility treatments.
• AMH levels have been found to be two to three times
higher in PCOS women , making it difficult to find a
threshold value for poor ovarian reserve without a
significant overlap with normal values.
Dynamic tests
Another approach towards identifying ovarian reserve
involves dynamic testing. This involves taking a baseline
serum sample, stimulating the ovaries
(FSH/Clomiphene/GnRH agonist) and then retesting the
serum level again for the same marker. All the dynamic
tests are more expensive, invasive and associated with
the side effects of administered stimulation regimens.
Combination of tests
Combinations of various markers (AFC, AMH and inhibin-B)
have been tried, and a joint scoring system has been
developed which predicts a poor response to
gonadotrophin stimulation at best with 87% sensitivity
and 80% specificity and a positive likelihood ratio of
4.36%. However, they have not been tested for
prediction of pregnancy .
THANKS

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