OVARIAN RESERVE AND INFERTILITY

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Ovarian Reserve

• Dr. Angelo Smith M.D
• WHPL

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General Facts

• Women are very different to men with regard to
  reproductive ageing.
• A womans entire lifetimes supply of eggs is
  present at birth.
• Decreasing ovarian reserve is inevitable with
  increasing age, resulting in complete infertility
  by age 40-50.
• Decreasing ovarian reserve has a significant
  negative effect on a couples reproductive
  prospects from age 37 onwards but earlier for
  some women.
• Ovarian reserve is a measure of how well the
  ovaries are still functioning at a certain point
  in time.

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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.

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Ovarian Reserve
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• 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.

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• 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

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Measures of Ovarian Reserve

• FSH (Follicle Stimulating Hormone)
• - lower is better (Normal lt10 iu/L)
• test cycle day 2-4
• fluctuates between cycles when ovarian reserve
  poor
• AMH (Anti Mullerian Hormone)
• higher is better (normalgt5pmol/L)
• less fluctuation between cycles

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• Antral Follicle Count (AFC)
• higher is better
• 5-10 AFs per ovary normal reserve
• lt3 AFs per ovary poor reserve
• gt10-15 AFs per ovary polycystic
• Menstrual cycle length
• Shortening cycles indicate deteriorating ovarian
  reserve.

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• Age and fertility
• In many cases, a womans age is the single most
  important indicator of fertility potential. A
  womans 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.

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• 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 .

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• 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.

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• 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 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.

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• 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 sertoli cells of the
  testes of men.
• It was thought not to exist in women. In recent
  years, it has been found in women starting at
  puberty.

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Reference range in Male
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
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• 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

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Amh Production
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 follicle selection
occurs.
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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
1345 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
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• 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.

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• 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.
•  

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• What are the factors that influence AMH levels?
• Factors that decrease AMH
• Increasing age
• Obesity
• Administration of gonadotropins
• Administration of chemotherapy or radiation
• Surgical removal of one or both ovaries
• B. Factors that increase AMH
• Polycystic Ovarian Syndrome

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• 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.

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• 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.

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AMH levels and pregnancy chances with in vitro
fertilization

• 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.

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PCOS AMH

• Pre- antral and small antral follicles produce
  AMH
• x6 the density of pre-antral follicles compared
  with the normal ovary in PCOS. (Webber et al,
  2003)
  
• High AMH levels in PCOS also due to increased
  production by individual
  follicles (Pellatt et al, 2007)
  
• Some have suggested that asymptomatic polycystic
  morphology (PCOM) is not an entity but a mild
  variation of normal.

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Anovulation

• A excess LH insulin
• Multiple small follicles
• AMH
• FSH action
• Anovulation
  progesterone

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