Testing Ovarian Reserve

Pregnancy Miracle

Pregnancy Miracle By Lisa

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James P. Toner

Atlanta Center for Reproductive Medicine, Atlanta, Georgia, U.S.A.

INTRODUCTION

Both the quantity of eggs and their quality are strong influences on IVF outcome. Markers of ovarian reserve, such as basal follicle-stimulating hormone (FSH) and basal antral follicle (BAF) 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 among those 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 quality; 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.

Seventeen years ago, Muasher and Oehninger from the Norfolk in vitro fertilization (IVF) program reported that basal follicle-stimulating hormone (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 assisted reproductive technology (ART). Although, there have been important refinements to our original understanding, the essence of the initial message has only been confirmed in the numerous studies that followed. In this chapter, 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

Ovaries contain all the eggs they will ever have before birth. Depletion of this supply begins before birth, and continues until menopause, when the endowment is gone (Fig. 1). The rate of this depletion is fairly constant over a woman's life span, but accelerates at around 37 years of age on average. At the beginning of every menstrual cycle, a fixed proportion of all remaining eggs acquires gonadotropin sensitivity. In natural cycles, all but one of these recruitable eggs undergo atresia, but the size of the recruitable cohort correlates with the woman's age. Given that the overall number of eggs in younger women is higher than in later years, the size of the cohort of recruit-able eggs in younger women is much larger.

As the number of remaining eggs decrease 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 et al. (4) have confirmed that the number of visible antral follicles on ultrasound correlates with the actual number in the primordial follicle pool.

Figure 1 At birth, a women has all the eggs she will ever have, and steadily looses them thereafter, until none remain at menopause. As her age increases and the supply diminishes, fertility declines. This fall in fertility is often signaled by a rise in basal FSH levels. Abbreviation: FSH, follicle-stimulating hormone.

Figure 1 At birth, a women has all the eggs she will ever have, and steadily looses them thereafter, until none remain at menopause. As her age increases and the supply diminishes, fertility declines. This fall in fertility is often signaled by a rise in basal FSH levels. Abbreviation: FSH, follicle-stimulating hormone.

Figure 2 The basal FSH level at the beginning of menstrual cycles can be divided into three phases. In the first phase, fertility is normal and FSH is always low. In the second phase, FSH is intermittently elevated and fertility is declining. In the last phase, FSH is always elevated and fertility is nil. Abbreviation: FSH, follicle-stimulating hormone.

Figure 2 The basal FSH level at the beginning of menstrual cycles can be divided into three phases. In the first phase, fertility is normal and FSH is always low. In the second phase, FSH is intermittently elevated and fertility is declining. In the last phase, FSH is always elevated and fertility is nil. Abbreviation: FSH, follicle-stimulating hormone.

One clinically useful indicator of follicle depletion is elevated FSH. Although basal (i.e., days 2-5 of the menstrual cycle) FSH fluctuates somewhat from cycle to cycle, three phases are distinguished: (i) Up until the time that egg supply begins to become limited, basal FSH is never elevated. (ii) Once menopause is well established, basal FSH is always elevated and (iii) During the intermediate stage, FSH is sometimes elevated and sometimes normal (Fig. 2). During this intermediate phase, however, fecundity is reduced whether or not the FSH is elevated during a particular cycle. Several studies have demonstrated that the ovarian response and the pregnancy rate in cycles with normal FSH is low 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 IVF, deliveries in women past age 42 years are uncommon, and past 45 years are rare.

2. High FSH is limiting even with normal age. The original reports saw a declining pregnancy rate as FSH rose above 20IU/L and no ongoing pregnancies beyond an FSH of 25IU/L (5,6). Although the assay has since changed and altered these cutoffs, there is still 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. Although this higher cutoff is not commonly reached [only 5% of cases in one study (7)], it reliably predicts low delivery rates.

3. Cutoffs for FSH depend on the lab test employed. Up through the early 1990s, the most commercial assays reported FSH levels about twice as high as those now in wide use. However, the typical assay method switched from a standard radioimmunoassay to a double antibody approach, and the assay standard changed. Consequently, the normal FSH cutoff of 20 IU/L is now just 10IU/L.

4. The highest FSH is the best predictor of ovarian reserve. 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 (7-9). 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 (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%) (5,10,11). In this regard, FSH is a better guide to selecting stimulation strength than who will become pregnant with treatment.

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 (12-16). Age, on the other hand, is the better predictor of embryo implantation and miscarriage rate (13,16-18). As prospects for delivery are affected by both quantitative and qualitative deficiencies in eggs, both age and FSH are important (Fig. 3).

^ Number of Good Embryos-►Delivery rate

Figure 3 The chance for successful pregnancy outcome in in vitro fertilization (IVF) is influenced by both quantitative and qualitative factors regarding eggs. The quantitative aspect seems best predicted by various markers of ovarian reserve such as basal FSH. The qualitative aspect seems best predicted by maternal age, and is manifest in implantation rates. Abbreviation: FSH, follicle-stimulating hormone.

Initial claims (by this author) that FSH was more predictive of outcome than age reflected a lack of understanding that both ovarian reserve and age are important independent predictors. The apparent strength of one over the other in any particular study has more to do with the ranges of FSH levels and age in a particular 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 (7,11,19,20). For instance, in one large study, high FSH levels were associated with a very low pregnancy rate (2.7%) even among women under age 35 years (21). And women aged 43 years or more have delivery rates under 3% per attempt in every annual report of U.S. ART outcomes. Clearly both factors are important predictors.

2. Young women with moderate elevations of FSH will make fewer eggs and have a higher 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 (5), but has been seen repeatedly since (22-26) as described below.

For example, the van Rooij et al. study (23) noted that in women under age 40 years with elevated FSH, the risk for cancellation was high, but the pregnancy rate among those proceeding to transfer was good (Table 1).

In another informative study (27), 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 2). However, as FSH became markedly elevated, pregnancy rates fell as stimulation adjustments were unable to compensate for diminished ovarian responsiveness.

Table 1 Comparison of Outcomes in Younger Patients with Diminished Ovarian Reserve to Older Patients with Normal Ovarian Reserve

<40 years with FSH 15+

41 + years with FSH <15

N

36

50

% canceled

31

8

% embryos implanted

34

11

% clinically pregnant

40

13

% ongoing pregnant

25

10

Abbreviation: FSH, follicle-stimulating hormone. Source: From Ref. 23.

Abbreviation: FSH, follicle-stimulating hormone. Source: From Ref. 23.

Table 2 Influence of Basal Follicle-Stimulating Hormone on Ovarian Response and Pregnancy Outcomes

Table 2 Influence of Basal Follicle-Stimulating Hormone on Ovarian Response and Pregnancy Outcomes

<10

10-15

15-20

20+

No. of amps

27.6

38.2

Estradiol at hCG

2391

1277

No. of eggs retrieved

13.1

6.5

No. of good embryos

2.9

2.5

2.1

1.7

Clinical pregnancy rate (%)

24.6

23.4

13.6

5.7

Live birth rate (%)

19.6

18.2

13.6

2.9

Abbreviations: FSH, follicle-stimulating hormone; hCG, human chorionic gonadotrophin.

Abbreviations: FSH, follicle-stimulating hormone; hCG, human chorionic gonadotrophin.

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 Figure 4. Note that women beyond age 42 years are unlikely to deliver no matter what their basal FSH might be; this reflects the significant reduction in egg quality (i.e., implantation

Chance Pregnancy Age And Fsh

Figure 4 Simultaneous consideration of age and FSH is important for understanding the chance for successful pregnancy in vitro fertilization (IVF) (theoretical model). High age (> 42 years) is a significant impediment no matter what the ovarian reserve, but high FSH also compromises success. Note that in young women, the success rate exceeds that for older women even when FSH is elevated. This supports the observation that in young women, even a few eggs can be sufficient; these women can and should be given the chance to try IVF as long as they are counseled regarding the increased risk of cancellation. Abbreviation: FSH, follicle-stimulating hormone.

Maternal age (y)

Figure 4 Simultaneous consideration of age and FSH is important for understanding the chance for successful pregnancy in vitro fertilization (IVF) (theoretical model). High age (> 42 years) is a significant impediment no matter what the ovarian reserve, but high FSH also compromises success. Note that in young women, the success rate exceeds that for older women even when FSH is elevated. This supports the observation that in young women, even a few eggs can be sufficient; these women can and should be given the chance to try IVF as long as they are counseled regarding the increased risk of cancellation. Abbreviation: FSH, follicle-stimulating hormone.

potential) which is nearly universally seen at this age independent of predicted or actual ovarian responsiveness. Also note that although younger women's success is dependent on basal FSH, even those with FSH elevations have a chance for pregnancy.

3. Other Markers of Ovarian Reserve a. An exaggerated FSH/luteinizing hormone (LH) ratio, even with normal FSH, is a sign of diminished ovarian reserve. In fact, the ratio of FSH/LH appears to be a clinically useful index, suggesting a PCO-like high response when LH exceeds FSH on one end of the spectrum, to diminished ovarian reserve when FSH exceeds LH (29-32) at the other. It is interesting to note that some PCO will develop regular cycles as their egg supply declines (33), as their FSH levels rise and their inhibin B levels fall.

b. Decreased early follicular phase inhibin B levels may occur before increases in FSH are observed (34).

c. Antral follicle count is a good predictor of ovarian reserve (35-38), and in some but not all studies appear better than the usual endocrine markers (including FSH) (35-39). Cancellation rate and egg production are better predicted by the antral follicle count than pregnancy rate. Ovarian volume seems less predictive than the follicle count (40).

d. Increased day 3 estradiol has been associated with both diminished ovarian reserve and enhanced ovarian reserve (ala PCO). This makes interpretation of this test problematic without further information. Those with diminished ovarian reserve display a high estradiol because of hurried folliculo-genesis and will have a low antral follicle count. Those with PCO can display a high estradiol as their many antral follicles each make a bit of estradiol. Interestingly, cancellation is increased with either low (<20 pg/mL) or high (>80 pg/ mL) estradiol levels (41,42), but these levels did not predict pregnancy rate in those not canceled. The combined FSH and estradiol in screening for diminished ovarian reserve appears to be more sensitive than either test alone (43).

e. Provocative tests of ovarian reserve, such as exogenous FSH ovarian reserve test (44), GnRH agonist stimulation test (45), and Clomiphene citrate challenge test (CCCT) (46) are more sensitive indicators of ovarian reserve than basal tests. Among these, the CCCT seems to best predict ovarian reserve (47,48). A large meta-analysis (49) recently showed both FSH and the CCCT to be highly specific (each >98%, i.e., an abnormal test result predicting no pregnancy); however, the CCCT was more sensitive (detecting about 25% of those not pregnant vs. only 6% for FSH alone). In the CCCT, an abnormal day 10 appears to carry the same poor prognosis as does an abnormal day 3; the prognosis is even worse if both are abnormal (50). f. Premature luteinization and a short follicular phase can be signs of diminished ovarian reserve (38,51,52).

4. Miscarriage risk is increased in those with diminished ovarian reserve (53-55).

5. Birth defect risks may be increased in those with diminished ovarian reserve (56).

6. Ovarian Reserve Effects in Natural Cycles. In a small study (n = 129) of a general population of couples trying to conceive, FSH was not predictive of pregnancy or miscarriage (57). Even in general subfer-tility population, one small study of women with an FSH > 10IU/L did not predict more time to pregnancy, fewer pregnancies, or fewer deliveries over a year's effort to conceive naturally (58). In another similar study of 103 young couples (average age of 33.2 years), pregnancy in the first year of unassisted reproduction was influenced by the woman's age, but not basal FSH, estradiol, or the basal follicle count (59). Insofar as natural cycles generally produce and release only one egg and that markers of ovarian reserve are more predictive of egg production capacity than egg quality, this absence of effect in unstimulated cycles is not surprising.

7. When an Elevated FSH does not Signal Trouble. On occasion, an elevated FSH may not signal quantitative limitations in egg production capacity per se, such as in cases of familial twinning or in the presence of heterophilic antibodies to FSH. Further, although in many cases a rise in FSH signals both quantitative and qualitative reductions in eggs, after ovarian tissue loss (surgical extirpation for cysts, endome-triomas, etc.), one would expect only a quantitative reduction.

CONTROVERSIES

Is BAF a Sufficient Test?/Can We Abandon Day 3 Bloods?

For predicting the number of eggs retrieved, basal antral follicle count (BAF) may be the best single test, but endocrine markers (FSH and inhibin) add additional predictive power to BAF alone (34). In this study, egg number was not predicted by age, basal E2, and total ovarian volume.

Since the Predictive Power for Delivery is Low, does any Testing Matter?

IVF is an expensive and inconvenient remedy for infertility. Basal markers such as FSH and BAF are good guides for ovarian response potential and are an important tool for picking a stimulation protocol of appropriate strength. And although our ability to predict pregnancy is generally poor with these same markers, there remains a small group with high FSH levels whose chance for pregnancy is almost nil (11). For instance, in the original study of 1478 cycles, those with a basal FSH over 25IU/L (5% of the group) had a 5.5-fold increase in poor response and a 12-fold increase in nonpreg-nancy outcome (5). Such effects are not unimportant, even if they identify a small subset of the entire IVF population.

SUMMARY

Various means of predicting ovarian response have been identified. Of these, basal FSH and ultrasound estimates of antral follicle count are the most useful. Adjusting stimulation strength to the expected ovarian reserve is a useful clinical practice. However, ovarian reserve is a relatively weak predictor of pregnancy potential, except when it is extremely low (which is uncommon overall). In the bulk of cases, maternal age is an important influence on pregnancy potential that operates independent of ovarian reserve (although the two are in many cases confounded).

As a rule of thumb, FSH and BAF are better predictors of ovarian reserve than is the age of the women, whereas age is a better predictor of the implantation potential of resulting embryos.

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, although their risk of cancellation is increased. In women past age 40 years, normal ovarian reserve testing is not particularly reassuring because reduced egg quality is likely to limit the opportunity for successful pregnancy even when many eggs are available.

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