OVARIAN RESERVE

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OVARIAN RESERVE AND INFERTILITY

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Ovarian Reserve:

Ovarian Reserve Dr. Angelo Smith M.D WHPL

General Facts:

General Facts Women are very different to men with regard to reproductive ageing. A woman’s entire lifetime’s 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 couple’s 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.

Definition:

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

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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     

Measures of Ovarian Reserve:

Measures of Ovarian Reserve 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

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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 deteriorating ovarian reserve.

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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.

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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.

Reference range in Male:

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

Amh Production:

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 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

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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.

AMH levels and pregnancy chances with in vitro fertilization:

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.

PCOS & AMH :

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.

Anovulation:

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

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