Unit 2. Biomarkers of ovarian reserve

Transcription

1 Unit 2 Biomarkers of ovarian reserve

2 Ovarian reserve: 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. Ovarian reserve is a complex clinical phenomenon that is influenced by age, genetics, environmental variable. 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.

3 Fertility and Infertility Rates fertility rates : age : 4% to 8% age : 1% to 19% age : 26% to 46% age : 95% Infertility rates: overall : 2.4% after age 34 : 11% after age 40 : 33% by the age 45 : 87%

4 Egg Quantity Egg Quantity Egg quantity refers to the number of eggs that you have in your ovaries Germ cells in the female are not replenished during life The number of oocytes and follicles is determined in utero and declines following an exponential curve from the second trimester to menopause

5 Egg Quantity During fetal life, germ cells rapidly proliferate by mitosis to yield approximately 6 to 7 million oogonia by weeks of pregnancy Transformed to oocytes after entering the first meiotic division, the number of germ cells falls to between 1 and 2 million at birth and to about 300,000 to 500,000 by the onset of puberty years of reproductive life: 400 to 500 oocytes Until age : approximately 25,000 oocytes Menopause time: <1,000 follicles

6 Egg Quantity

7 Egg Quality Egg Quality refers to the ability of eggs to become fertilized. Eggs in ovaries need to have the right shape, health, and chromosomes in order to be able to develop into an embryo. Unfortunately, egg quality also changes over time becoming weaker and less able to form a healthy embryo The number of eggs available for fertilization decrease in an age-dependent manner.

8 Is it possible to predict the ovarian reserve? Ovarian Reserve Tests Biological Biochemical Biophysical Histological Chronological Age Static Dynamic Ultrasound Ovarian Biopsy - FSH - FSH : LH - E2 - AMH CCCT - Antral follicle count - Ovarian volume - Ovarian blood flow

9 Is it possible to predict the ovarian reserve? Markers of ovarian reserve: static tests Age Basal serum FSH Basal serum estradiol Basal LH/FSH ratio Basal serum inhibin-b level Basal serum anti-müllerian hormone level Basal ovarian volume Basal antral follicle count Ovarian stromal blood flow

10 Is it possible to test the ovarian reserve? Dynamic tests Clomiphene citrate challenge test (CCCT) GnRH agonist stimulation test (GAST) Exogenous FSH ovarian reserve test (EFORT)

11 Day 3 FSH Test 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). 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.

12 Antral follicle count measurement 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.

13 Antral follicle count measurement 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.

14 Anti-Müllerian hormone (AMH) Anti-Müllerian hormone (AMH) is a glycoprotein growth factor and a member of the transforming growth factor superfamily(tgf-b) with a molecular weight of 140kDa. AMH is produced by the granulosa cells of the recruited follicles, until they become sensitive to FSH. 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.

15 Anti-Müllerian hormone (AMH) AMH is expressed in granulosa cells of primary, preantral and small antral follicles, while its expression disappears in antral and atretic follicles. Expression is lost last in the granulosa cells surrounding the oocytes.

16 Anti-Müllerian hormone (AMH)

17 Anti-Müllerian hormone (AMH) The decrease of AMH levels is correlated to the age. AMH levels correlate well with the ovarian antral follicle count and are the only levels that decreased longitudinally over time compared with FSH, estradiol, and inhibin-b levels. AMH levels decrease with ovarian aging, followed by a decline in inhibin-b and finally by an increase in FSH levels.

18 Anti-Müllerian hormone (AMH) Several factors can affect the AMH serum by decreasing its levels Increasing age Obesity Administration of gonadotropins Administration of chemotherapy or radiation Surgical removal of one or both ovaries

19 Anti-Müllerian hormone (AMH) Several factors can affect the AMH serum by increasing its levels Polycystic Ovarian Syndrome Several factors do not affect AMH levels: Day of menstrual cycle GnRH agonists Birth Control Pills Pregnancy

20 What are normal and abnormal levels of AMH? AMH levels less than 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.

21 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.

22 Advantages and disadvantages for AFC and AMH level

23 Dynamic tests 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. A test that can provide earlier evidence of declining ovarian function is the clomiphene citrate challenge test (CCCT), that is similar to a "stress test" of the ovary.

24 CCCT Measuring a basal Day 3 FSH and estradiol level. Administering 100 mg of clomiphene citrate from Day 5 to Day 9. Measuring Day 10 FSH and estradiol level. Elevated levels of FSH on either Day 3 or Day10 of the cycle suggests that ovarian reserve is poor. If the sum of the FSH levels is more than 25, then this suggests poor ovarian function

25 Dynamic tests: disadvantages Invasive Expensive, Associated with the side effects of administered stimulation regimens.

26 Ovarian Reserve Tests: VIDEO