In order to adequately counsel women experiencing infertility about their prognosis, as well as to determine which treatment might serve them best, reproductive endocrinologists routinely perform some screening tests to assess their patients’ ovarian reserve. What is ovarian reserve? It is basically an estimate of how many oocytes (eggs) are left in the ovaries, and that often translates into how many eggs are we going to be able to work with over the course of any given monthly treatment.
The ovary, as miraculous a structure as it is, is unfortunately very wasteful. Every month it calls forth from within itself a troop of immature eggs, only one of which is destined to ovulate. Depending on how vast your ovarian reserve is, that starting “troop” can range from one or two to sixty or seventy. The one egg that’s “chosen” to ovulate resides within an ever-enlarging ovarian follicle or cyst that is readily visible on ultrasound by mid-cycle. Ultimately when that dominant follicle gets big enough, say about 2 centimeters, it will rupture or ovulate. When all is perfect, the mature egg will then get picked up by the nearby fallopian tube, be fertilized by sperm, and make its way into the uterine cavity where it will burrow in and make a baby. All the other eggs that were recruited will die, a process called atresia. That’s why women are essentially devoid of eggs by age 50 despite only ovulating about 400 eggs over the course of their lifetimes.
Ovarian reserve is generally correlated with age; i.e. a woman in her forties will have very diminished ovarian reserve while a woman in her twenties should have excellent ovarian reserve. However, there is such a tremendous amount of individual variation that other factors have been sought to help elucidate ovarian reserve better. Several hormones with predictive power have since been described and are now an almost indispensable part of fertility assessment.
Along with a depletion in egg numbers, there is a decrease in egg quality with time, and this is the major factor limiting success in older women. Egg quality refers in general to chromosomal normalcy, and age predicts relative egg quality better than ovarian reserve screening. Therefore, a younger woman with poor ovarian reserve will still have a better chance at getting pregnant than an older woman with the exact same results because her egg quality will generally be better. Age is an independent predictor of IVF outcome and is more closely related toimplantation and ongoing pregnancy rates than the hormonal reserve markers.
The hormone most often used to gauge ovarian reserve is the day 2 or 3 Follicle Stimulating Hormone (FSH) level. Think of FSH as the wake-up call for the ovary; if the ovary is responsive then the amount of FSH needed to get the ovary up and running is minimal (a good scenario). If the ovary is non-responsive (i.e. few developing follicles with a commensurately low level of estradiol and inhibin being made), then the pituitary gland tries to compensate for this by pumping out a large amount of FSH (a bad scenario). When the ovary completely runs out of eggs in menopause, the amount of FSH in the bloodstream is very elevated to the point where it can be over ten times that of a woman in her twenties.
FSH is also an independent predictor of IVF outcome, correlating mainly with the number of retrieved oocytes. Recent studies have shown that young women with high FSH levels demonstrate lower numbers of growing follicles but can still achieve good pregnancy rates if oocytes and embryos are obtained. This highlights the premise that age best reflects egg quality better than FSH levels.
Estradiol is usually measured simultaneously with basal FSH. Even if the basal FSH is normal, estradiol elevations greater than 70 pg/mL are also associated with poor response to ovarian stimulation. Elevated early follicular phase estradiol levels may indicate an inappropriately advanced stage of follicular development, a sign of ovarian aging whose clinical manifestation is a shorter menstrual cycle. This situation can also occur if the patient has misjudged her cycle timing or has an estrogen secreting (“functional”) ovarian cyst.
A recent addition to the list of promising candidates for predicting ovarian response is anti-müllerian hormone (AMH), also known as mullerian inhibiting substance (MIS). MIS is produced in the ovary by granulosa cells of growing preantral and small antral follicles. MIS concentrations correlate well with antral follicle count and age, and at the present moment, seems to constitute the most sensitive marker of ovarian aging. Indeed, it has been shown that poor response in IVF is associated with decreased MIS levels. An added benefit of MIS assessment is that it does not fluctuate over the course of any given menstrual cycle so it can be drawn at any point irrespective of cycle timing.
The antral follicle count or AFC is the number of antral follicles (small egg-containing ovarian cysts) visible by transvaginal ultrasound in the early follicular phase of the cycle. The AFC decreases with age and provides perhaps the best single prognostic indicator for poor response during IVF. A normal AFC for a woman in her twenties to thirties is somewhere in the range of 12 to 16. Women with polycystic ovarian syndrome (PCOS) often have AFCs greater than 50, and it is therefore not surprising that when challenged with gonadotropin medication their response in terms of egg number can be astronomical.
Several “challenge” tests have been designed that offer the theoretical benefit of measuring ovarian reserve in a dynamic, and perhaps more clinically representative way. The clomiphene citrate challenge test (CCCT) is the most commonly used of these and involves the administration of 100 mg clomiphene citrate on days 5 to 9, and the measurement of FSH levels on days 3 and 10. An abnormal test is defined as an abnormally high FSH on day 10. With basal FSH and the CCCT, a normal result is of little predictive value, but an abnormal result is predictive of poor outcome from infertility treatment. Given that the CCCT offers no clear advantage over and above a single basal FSH measurement, a basal FSH measurement seems adequate.
When all is said and done, the best estimate of ovarian reserve is derived from actually treating a patient and observing her relative responsiveness to the medication administered. It therefore pays to monitor each patient very carefully over the first several days of treatment so medication can be adjusted accordingly.
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