Research, experience and analysis of treatment data are helping us deepen our knowledge and evolve our testing of ovarian reserve. We know now that using day 3 FSH alone can be an inaccurate predictor of fertility potential, especially in younger women with elevated day 3 FSH, and that a much clearer picture emerges when antral follicle count (AFC), day 3 FSH levels and the patient age are combined. This new insight has resulted more individualized treatment protocols and better outcomes for many of our patients.
Testing Ovarian Reserve
There are a number of tests that infertility specialists can use to assess the female partner’s “ovarian reserve” during an infertility evaluation. The term “ovarian reserve” refers to what remains of oocyte number and function after the natural effects of aging and depletion. We use this important information to define prognosis of the treatment options and select the treatment medication protocols. As we know, women are born with their full complement of oocytes at birth and do not make more, unlike men who continue to make new sperm through much of life.
A woman’s ovary is programmed to lose many oocytes through atresia throughout her reproductive years, even starting pre-pubertally and continuing on until menopause, when the ovaries are essentially devoid of these germ cells. As the female progressively ages, not only does her oocyte count deplete more rapidly, but also the chromosomes within the oocytes (which have been arrested in a delicate mid-meiotic division) become more prone to chromosomal anomalies. This leads to increasing embryo aneuploidy from the aging oocytes, and is, of course, the reason for the recommendations for pre-natal genetic testing in pregnancy when over 35 years old. In addition, increases in infertility rates and in miscarriages accelerate at ages 35-39, with much greater problems thereafter. Spontaneous pregnancy after the age of 45 is very unusual.
The degree and speed of ovarian aging is specific to the patient and is partially genetically predetermined. Although several environmental factors, e.g. cigarette smoking, chemotherapy, certain medications, and drug use can accelerate ooctye atresia and aneuploidy, unfortunately there is nothing we can do to improve or delay it. Our therapeutic regimens and medications are designed to stimulate the maturation of more eggs in a cycle of therapy by rescuing them from atresia and in this way can help the couple maximize the use of a larger cohort of eggs/embryos from what oocytes remain.
Evolution in Ovarian Reserve Testing
The two best tests we currently use to determine ovarian reserve are the antral follicle count (AFC)and the day 3 FSH concentration. We also look at day 3 estradiol and LH levels for adjunctive information and, in older patients we may add the Clomid Challenge Test. This latter dynamic test can be used to unveil underlying decreases in ovarian reserve just as a Cardiac Stress Test can be used in addition to a resting EKG. Additional tests of ovarian reserve are being evaluated, such as serum Inhibin and Anti Mullerian Hormone testing, but we will discuss the two most commonly in use today for our patients: the AFC and day 3 FSH.
While the antral follicle count has recently been shown to be an excellent predictor of fertility potential, combined with the day 3 FSH they complement each other in helping us predict outcomes and protocols for our patients. The antral follicles are the 2-10mm follicles within the ovarian stroma that represent the next waves of ovulation and can be visualized on a day 3 tranvaginal ultrasound. In general, the more antral follicles we visualize, the better prognosis for the patient. We like to see at least 10 follicles between both ovaries. If we see less, we know that we will need to alter our prognosis for the patients and recommend more aggressive treatment protocols. If we see many more (i.e. PCOS patient), then more conservative dosing protocols are warranted, even in IVF.
The day 3 FSH concentration has repeatedly been shown to be a significant predictor of ovarian reserve. We know that an elevated baseline day 3 FSH level indicates a poor prognosis and lower response to ovarian stimulation in patients over 35. But is this also true in a patient in her 20’s or early 30’s? More recent evidence has led to an evolution in our discussions with patients as we have learned that the day 3 FSH has different predictive value in the younger infertility patients compared with those older.
Younger Age “Trumps” Elevated Day 3 FSH in Predicting Treatment Outcome
We know that age and FSH are both independent predictors of ovarian reserve, and the chart below of three different age patients, each with a normal FSH or each with an elevated FSH, may illustrate this.
|Patient Age :
|Day 3 FSH :
|Day 3 FSH :
In the above examples, the 30-year-old patient with an FSH of 7 has the best prognosis and the 40-year-old with an FSH of 14 the worst. But the 40 y/o with an FSH of 7 has a poorer prognosis than the 30 y/o with that same FSH, due to the independent effect of age and FSH. Likewise, the prognosis for 30 y/o with the elevated FSH is not what it might be at her same age with a normal FSH, but what we have learned from experience is that this younger patient’s prognosis, despite the elevated FSH, is still quite good. To achieve that prognosis might require a stronger stimulation protocol to her ovaries, as she would likely respond less vigorously to medication with fewer eggs. Thus, age is somewhat protective for most young patients, even with moderately elevated FSH levels.
Aggressive Ovarian Stimulation Helps Younger Patients with Elevated FSH
The first study to address what is summarized above was a study by Esposito et al. where we found that elevated FSH levels best predicted poor pregnancy outcomes in women older than 35 years of age. But we also found that younger patients with elevated FSH had a higher chance of cycle cancellation due to poor response, but that if we stimulated them more aggressively in the IVF cycle with more aggressive treatment protocols, they could have a reasonable chance of becoming pregnant. More studies have come out supporting this.
The bottom line for day 3 FSH testing seems to be the following: Moderately elevated FSH levels in younger patients likely means fewer oocytes in the ovaries but, since the patient is young, the egg quality may still be good. A good AFC helps predict a better outcome for her. Elevated FSH levels in older patients, especially when combined with lower AFC, are more of a concern as they are correlated to poorer oocyte quality in the fewer number of oocytes available. Older patients with elevated FSH levels are best served statistically by the use of donor eggs.
Thus, experience and data are helping us evolve our testing of ovarian reserve, especially using AFC plus day 3 FSH levels plus the patient age. This has led to more accurate individualized prognosis for outcomes and better-individualized treatment protocols. In the next few years, Ovarian Reserve assessment may also include new tests and continued evolution in how we interpret them to better counsel and treat our patients.