Aging and Infertility. Part 2. National Infertility Centre Dr. Vincenzo Noto National Infertility Centre Tripoli Symposium on Infertility Tripoli, March 20 – 21, 2009

Assessing Reproductive Age The Tests What are you measuring when assessing the reproductive age? And why? Reproductive performance To predict the response to stimulation To have an estimate of the live-born

Ovarian Reserve Testing Goal: To determine the functional capacity of the ovary. Specifically the quantity and quality of oocytes remaining. General Population To predict the chance of conception. Determine the time before ovarian aging begins. Sub-fertile Population Chance of conception, with or without treatment. Optimal dose or protocol for treatment. Maheshwari, et al, 2006

Aneuploid Embryos Can Develop Normally Until Day 5 of Life! Development of Embryo with Trisomy 21, determined by PGD on day 3, with develoment to normal-appearing blastocyst.

Testing Ovarian Reserve A mathematical model for assessment of a woman’s reproductive lifespan has been proposed by a group of investigators from the University of Andrews, Scotland. Chronological age and ultrasonagraphic ovarian characteristics are incorporated into the model to determine the “Reproductive age” of the patient. Model is designed to tell a patient when she may transition into menopause. Time to menopause may not provide an accurate assessment of years of fertility remaining.

Ovarian Reserve Reproductive endocrinologists face the challenge of providing patients with an adequate prognosis of their fertility potential at a given age to avoid the following: Exposing patients to expensive and labor-intensive treatments that have little chance of success. Falsely discouraging patients from such treatments that might result in pregnancy.

Testing Ovarian Reserve Screening for ovarian reserve was an outgrowth of assisted reproductive technologies. Tests were initially designed to determine prognosis of in vitro fertilization, in terms of follicle recruitment and odds of pregnancy. Few tests have been validated in the general infertility population.

Testing Ovarian Reserve Ideal screening test for ovarian reserve should have the following characteristics: Capture all patients who are infertile (high sensitivity). Correctly identify those patients who are fertile (high specificity). Should test that component of the reproductive axis felt to be primarily responsible for decrease in fecundity.

In the case of testing ovarian reserve, high positive predictive value (PPV) and negative predictive value (NPV) are most important since the accuracy of the test can only be confirmed after pregnancy has been attempted. Barnhart K et al. Follicle stimulating hormone as a predictor of fertility. Curr Opinion in Obstetrics and Gynecology 1998; 10:227-32.

Septimus Severus Arch Leptis Magna

Assessing Reproductive Age Direct measures AFC/ovarian volume Anti-Müllerian Hormone (AMH) Inhibin B Indirect measures FSH

A different classification 1.

A different classification 2.

Clomiphene Challenge Test Provocative test of ovarian reserve first proposed as a screening test in 1989. Clomiphene Citrate is an estrogen antagonist at the pituitary gland and causes a rise in FSH levels. The test aims to determine if ovarian follicles are sufficient in quantity and quality to produce enough hormone to bring FSH back down to normal.

Clomiphene Challenge Test

Clomiphene Challenge Test FSH is checked on day 3 of the cycle. Clomiphene Citrate (100 mg) is administered from days 5-9 of the cycle. FSH is rechecked on day 10 of cycle. Scott RT et al. Prognostic assessment of ovarian reserve. Fertility and Sterility 1995;63:1-11.

Clomiphene Challenge Test Advantages: Non-invasive. Inexpensive. Sensitivity and negative predictive value improved over basal day 3 FSH testing alone (26%, 42%). Validated in IVF patients and general infertility population. Disadvantages: Slight decrease in positive predictive value compared to day 3 FSH, especially when used in low risk population (96%). Slight decrease in specificity compared to day 3 FSH (98%). Barnhart K. Curr Opinion in Obstetrics and Gynecology 1998;10:227-32

The Theatre - Sabratha

Day 3 FSH First proposed as a screening test in 1988. FSH is at its maximum in the early part of the menstrual cycle when estrogen levels are at their nadir. Elevated values suggest that ovarian follicles are not able to adequately suppress FSH. Values greater than 10mIU/ml correlate with poor prognosis for those going through IVF. cont………… Barnhart K. Curr Opinion in Obstetrics and Gynecology 1998;10:227-32

Day 3 FSH Indirect measure of follicular pool. Decrease in inhibin B leads to increase FSH. Not associated with increased risk of aneuploidy (van Mongfrans, 2004). Decreased predictive ability in populations with a low prevalence (young women).

Day 3 FSH Advantages: Non invasive. Relatively inexpensive. Better predictor of IVF outcomes than age alone. High positive predictive value (as high as 97%). High specificity (as high as 98.7%). Disadvantages: High intercycle variability. Poor negative predictive value (as low as 17%). Poor sensitivity (as low as 8%). Positive predictive value highly sensitive to population prevalence of infertility. Barnhart K. Curr Opinion in Obstetrics and Gynecology 1998;10:227-32.

AP Brown1, L Maddison1, C Fitzgerald2, D Gould2, L Nardo2 and I Laing1 1Department of Clinical Biochemistry, Manchester Royal Infirmary 2Department of Reproductive Medicine, St Mary’s Hospital, Manchester

AP Brown1, L Maddison1, C Fitzgerald2, D Gould2, L Nardo2 and I Laing1 1Department of Clinical Biochemistry, Manchester Royal Infirmary 2Department of Reproductive Medicine, St Mary’s Hospital, Manchester

AP Brown1, L Maddison1, C Fitzgerald2, D Gould2, L Nardo2 and I Laing1 1Department of Clinical Biochemistry, Manchester Royal Infirmary 2Department of Reproductive Medicine, St Mary’s Hospital, Manchester

AP Brown1, L Maddison1, C Fitzgerald2, D Gould2, L Nardo2 and I Laing1 1Department of Clinical Biochemistry, Manchester Royal Infirmary 2Department of Reproductive Medicine, St Mary’s Hospital, Manchester

The Red Castle – Tripoli Turkish Period

Antral follicle count AFC = 18 AFC= 4

Number of Antral Follicle count Clinical Pregnancy Rate

AP Brown1, L Maddison1, C Fitzgerald2, D Gould2, L Nardo2 and I Laing1 1Department of Clinical Biochemistry, Manchester Royal Infirmary 2Department of Reproductive Medicine, St Mary’s Hospital, Manchester

AP Brown1, L Maddison1, C Fitzgerald2, D Gould2, L Nardo2 and I Laing1 1Department of Clinical Biochemistry, Manchester Royal Infirmary 2Department of Reproductive Medicine, St Mary’s Hospital, Manchester

Inhibin B Inhibin inhibits FSH production and GnRH release in the anterior pituitary. FSH stimulates the secretion of inhibin from the granulosa cells of the ovarian follicles in the ovaries. In turn, inhibin suppress FSH. Inhibin secretion is diminished by GnRH, and enhanced by insulin-like growth factor-1 (IGF-1). Inhibin B reaches a peak in the early- mid-follicular phase, and a second peak at ovulation. Inhibin is produced in the gonads, pituitary gland, placenta and other organs. Decreasing inhibin production by aging or rapidly declining ovarian follicles may explain relationship between elevated FSH levels and declining fertility. Early investigations suggest that women with normal values are 6.8 times more likely to conceive even when age and day 3 FSH are accounted for a reduction of the ovarian reserve. Barnhart K. Curr Opinion in Obstetrics and Gynecology 1998;10:227-32.

AMH The Anti-Müllerian Hormone is a glycoprotein hormone secreted in mammals by Sertoli cells of the fetal testicle during the early phases of development and responsible for the regression of the Mullerian ducts. It can be measured in males during infancy and adult life. Not present in females until the puberty, when, secreted by the granulosa cells, controls the primary follicle formation, inhibiting the excessive follicular stimulation generated by the FSH. It has an important role in folliculogenesis and some authors suggest that is determination may be useful in some conditions like PCOS and Primary Ovarian Failure.

The Medina

Optimal test may be an index that incorporates several serum markers and non-serologic data

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