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Both quantitative and qualitative factors regarding egg production are strong influences on IVF outcome. Markers of ovarian reserve such as basal FSH, (CCCT), and antral follicle counts are good predictors of the quantity of eggs which can be induced to grow. However, the quality of those eggs seems better predicted by the age of the women. In women past age 40, current success rates are low overall, even in those who good ovarian reserve who make many eggs; at this age, quantity does not make up for quality.

By contrast, young women with limited ovarian reserve can have good success rates despite their limited cohort of eggs, because the eggs themselves are of high potential; here quality matters more than quantity. The ramifications of these observations include the following: Diminished ovarian reserve should not be used as an exclusionary criterion in young women, because overall they still have satisfactory pregnancy rates, though their risk of cancellation is increased. In women past age 40, normal ovarian reserve testing is not reassuring because even reduced egg quality is likely to limit the opportunity for successful pregnancy no matter how many eggs are available.

Fifteen years ago Muasher and colleagues from the Norfolk IVF program reported that basal FSH levels predicted ovarian response and pregnancy outcome in IVF cycles [1]. Since then more than a hundred articles have sought to refine our understanding of the link between markers of "ovarian reserve" and pregnancy in ART. And while there have been important refinements to our original understanding of the concept of ovarian reserve, the essence of the initial message has only been confirmed in the numerous studies that followed. In this article we will consider the biological basis for the links among the markers of ovarian reserve, the reserve itself, and the pregnancy potential. We will also review the original and newer elements of this understanding.

Physiology of Ovarian Reserve

Women make all the eggs they will ever have before they are born. This supply begins to be depleted before birth, and continues until menopause, when the endowment is gone (Fig. 1). Most studies have suggested that the rate of egg loss is essentially constant over a women's life span, although several reports have detected an accelerated rate of loss at around age 37 years on average. This means that at the beginning of every menstrual cycle, a relatively fixed proportion of all the remaining eggs becomes 'recruitable,' i.e., sensitive to gonadotropins. Given that the overall number of eggs in younger women is higher than at later years, the size of the 'cohort' of recruitable eggs in younger women is much larger.

As the size of the egg endowment decreases with age, certain predictable concomitants have been observed. These include physical manifestations, such as smaller ovaries and fewer antral follicles, but also hormonal events, such as elevations of basal FSH and shorter follicular phases [2,3]. Morris [4] has confirmed that the number of visible antral follicles on ultrasound correlates with the actual number in the primordial follicle pool.

Another feature of follicle depletion relates to the expected pattern of FSH rise. While 'basal' (i.e., days 2 to 5 of the menstrual cycle) FSH fluctuates somewhat from cycle to cycle, we can distinguish 3 phases: 1. Up until the time when egg supply begins to become limited, basal FSH is never elevated. 2. Once menopause is well established, basal FSH is always elevated. 3. During the intermediate stage, FSH is sometimes elevated and sometimes normal (Fig. 2). During this phase, however, fecundity is reduced whether or not the FSH is elevated during a particular cycle or not. Several studies have demonstrated that the ovarian response and pregnancy rate in cycles with normal FSH is not normal if any prior cycle displayed an abnormal FSH.

Original understandings:

Many elements of the initial reports are still valid, including:

1. High age is limiting even with normal FSH. Original reports demonstrated lower pregnancy rates in women past 40 years of age, no matter their basal FSH level [5]. Even with today's treatments, successful pregnancies past age 42 are uncommon, and past 45 are rare.

2. High FSH is limiting even with normal age. The original reports saw a declining pregnancy rate as FSH rose above 20, and no ongoing pregnancies beyond an FSH of 25 IU/L [5,6]. While the assay has since changed and altered these cutoffs, there still tends to be a threshold above which declining performance (egg production and pregnancy rate) is detected, and a higher threshold above which egg production is quite limited, and almost no pregnancies have occurred.

3. Cutoffs for FSH depend on the lab test employed. Up through the early 1990's, most commercial assays reported FSH levels about twice as high as those now in wide use. Thus, whereas the cutoff of normal FSH was 20 IU/L in early reports, it is now more commonly about 10 IU/L. And whereas markedly abnormal ovarian reserve was formerly seen only above 25 IU/L, now that threshold occurs above about 15 IU/L. It is still best if clinics develop their own thresholds to define then end of the normal range, and the entry into the very abnormal range, for FSH and estradiol assays commonly employed for their patients.

4. The highest-ever FSH is the one most likely to be true. Several early reports demonstrated the futility of delaying treatments until a cycle with a normal FSH occurs. More recent studies have continued to affirm this effect [7,8]. Once an FSH elevation is observed, egg production capacity will be limited thereafter. This is to be expected, given the on-again, off-again nature of basal FSH elevations once egg numbers become critically short (as illustrated in Fig. 2).

5. Prediction of ovarian reserve is easier than predicting pregnancy. Basal FSH levels are better able to predict outcomes more closely related to ovarian function, such as cancellation (R2=77%), follicles aspirated (R2=35%), and oocytes retrieved (R2=21%) than more distal events such as pregnancy rate (R2=4%) [5,9].

Refined understandings:

1. High age and high FSH affect delivery rates but in different ways. FSH is the better predictor of the number of eggs that can be induced to grow by gonadotropin administration, and consequently cancellation rate [10-14]. Age, on the other hand, is the better predictor of embryo implantation and miscarriage rate [11,14-16]. Since prospects for delivery are affected by both quantitative and qualitative deficiencies in eggs, both age and FSH are important (Fig. 3).

Initial claims (by this author) that FSH was more predictive of outcome than age, and similar subsequent claims, reflects a lack of understanding that both ovarian reserve and age are important. The apparent strength of one over the other in any particular study has more to do with the operating range of FSH and age in the cases under study than in any underlying physiological principle. Furthermore, at extremes of either age or FSH (e.g., age >45 years, FSH >20 IU/L), fertility is essentially nil [17-20]. In one large study of IVF patients, FSH >14.2 IU/L was associated with a very low pregnancy rate (2.7% and a high miscarriage rate (71.4%) which persisted even among women below age 35 years [21]. Annual reports of U.S. ART live born delivery rates in women over age 43 years are chronically under 3% per attempt. Clearly both factors are important predictors.

2. Young women with moderate elevations of FSH will make fewer eggs, and run a high risk of cycle cancellation, but if eggs are retrieved, they have reasonable chances for pregnancy. This 'protective' effect of young age was not seen in the original study (Toner 91), but has been seen repeatedly since [22-25].

For example, the van Rooij study [23] noted that in women under age 40 with elevated FSH, the risk for cancellation was high, but the pregnancy rate among those proceeding to transfer was good (Table I).

In another informative study [26], mild elevations of FSH predicted the need for more stimulation to get an acceptable ovarian response. Even with this adjustment, a lower response was in evidence, but enough eggs were produced to achieve a roughly equivalent transfer and pregnancy rate (Table II). However, as FSH became more elevated, pregnancy rates fell as stimulation adjustments were unable to compensate for diminished ovarian responsiveness.

It is also important to note that while FSH (and related endocrine or ultrasound markers) are the best available predictors of the quantity of eggs that can be produced, the actual number produced is more meaningful to outcome that the prediction. Thus studies that focus on cycles in which only a few eggs are produced show low success rates even at young ages [27] (Table III).

The strength of the relation between basal hormone markers and ovarian reserve is enhanced with luteal estradiol administration [28].

The combined effect of age and FSH on ultimate delivery rate is illustrated in the following Figure 4. Note that women beyond age 42 are unlikely to deliver no matter what their basal FSH might be; this reflects the significant reduction in egg quality (i.e., implantation potential) which is nearly universally seen at this age independent of predicted or actual ovarian responsiveness. Also note that while younger women's success is heavily dependent on basal FSH, only when the FSH is markedly elevated (typically above 20 IU/L) will their chances as low as the women in their mid-forties.

3. Other markers of ovarian reserve:

In summary, estimates of ovarian reserve have proved helpful in predicting pregnancy potential in ART, largely through their ability to predict the quantity of eggs which can be induced to grow. The quality of those eggs seems better predicted by the age of the women, and both factors are important. In women past age 40, current success rates are low overall, even in those who good ovarian reserve who make many eggs; at this age, quantity does not make up for quality. By contrast, young women with limited ovarian reserve can have good success rates despite their limited cohort of eggs, because the eggs themselves are of high potential; here quality matters more than quantity.

The ramifications of these observations include the following: Abnormal tests of ovarian reserve are the best predictors we have of egg production capacity, but are not perfect. Thus diminished ovarian reserve should not be used as an exclusionary criterion in young women, because overall they still have satisfactory pregnancy rates, though their risk of cancellation is increased. In women past age 40, normal ovarian reserve testing is not particularly reassuring because even reduced egg quality is likely to limit the opportunity for successful pregnancy even when many eggs are available.