Deg135 700.706

Human Reproduction Vol.18, No.4 pp. 700±706, 2003 The number of antral follicles in normal women with proven fertility is the best re¯ection of reproductive age G.J.Scheffer1,6, F.J.M.Broekmans1, C.W.N.Looman2, M.Blankenstein3, B.C.J.M.Fauser4, F.H.deJong5 and E.R.teVelde11Department of Reproductive Medicine, Division of Perinatology and Gynecology, University Medical Center Utrecht, 2Department of Public Health, Faculty of Medicine, Erasmus University, Rotterdam, 3Department of Clinical Chemistry, Free University Medical Center, Amsterdam, Division of Reproductive Medicine, 4Department of Obstetrics and Gynecology and 5Department of Internal Medicine III, Erasmus University Medical Center, Rotterdam, The Netherlands6To whom correspondence should be addressed at: Department of Reproductive Medicine, Division of Perinatology and Gynecology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail: [email protected] BACKGROUND: The purpose of this study was to compare the predictive capacity of several markers of repro- ductive age in normal women. METHODS: Healthy female volunteers (n = 162) aged 25±46 years with proven, normal fertility and regular menstrual cycles were recruited. In this selected group, chronological age was assumed to approximate reproductive age and, therefore, was taken as the proxy-variable for reproductive age. The number of antral follicles with 2±10 mm diameter, total ovarian volume, total follicular volume, mean follicular volume, and volume of either the smallest or largest ovary were estimated by transvaginal sonography of the ovaries. Serum levels of early follicular FSH, estradiol and inhibin B, as well as the response of estradiol and inhibin B to exogenous GnRH agonist administration (GAST), were also evaluated. RESULTS: Regression analysis revealed that the antral follicle number showed the highest correlation with age (r = ±0.68, P = 0.001), and explained 46% of its variance. All other variables, except inhibin B, were moderately correlated with age. Responses of estradiol and inhibin B to the GnRH agonist were moderately correlated with age, but highly correlated with the number of antral follicles.
CONCLUSIONS: It is concluded that the number of antral follicles has the closest association with chronological age in normal women with proven fertility. As stimulated estradiol and inhibin B clearly re¯ect the size of the antral follicle cohort, the GAST may be considered the second best single test to predict reproductive age.
Key words: antral follicles/GnRH agonist stimulation test/inhibin B/reproductive ageing/transvaginal sonography Corson et al., 1999; Hall et al., 1999; Creus et al., 2000), Delaying the period in life to have children considerably estradiol (E2) (Evers et al., 1998; Mikkelsen et al., 2001) and contributes to the proportion of couples with involuntary the E2 and inhibin B response to exogenous GnRH agonist childlessness (Mosher et al., 1991). Demographic (Wood, (GAST) (Winslow et al., 1991; Avrech et al., 1996; Galtier- 1989) and clinical (Noord-Zaadstra et al., 1991) studies have Dereure et al., 1996; Ranieri et al., 1998; Ravhon et al., 2000) shown that a woman experiences her optimal fertility before or FSH stimulation (EFORT) (Fanchin et al., 1994; Dzik et al., the age of 30±31 years. Thereafter, fertility gradually 2000; Fabregues et al., 2000; Elting et al., 2001) have all been decreases, with an acceleration towards the age of 40 years.
mentioned in the literature to predict declining fertility related Already at an age of 40±41 years half of the women will have to reproductive ageing. Most of these studies were performed completely lost their capacity for reproduction. It is generally in infertility populations, using pregnancy rates or response to accepted that reproductive ageing is in fact ovarian ageing and ovarian hyperstimulation in IVF as outcome measures.
is related to the decreasing quantity and quality of the pool of However, the establishment of a pregnancy is in¯uenced by follicles preserved in the ovary (Seifer et al., 1996; teVelde and many more, partly unknown, factors. To what extent ovarian ageing per se contributes to the reproductive failure of an The number of antral follicles and the total ovarian volume individual couple remains a matter of speculation.
as measured by transvaginal ultrasound (Lass et al., 1997; Studies concerning physiological ovarian ageing in women Tomas et al., 1997; Chang et al., 1998; Ng et al., 2000; Bancsi without fertility problems have only been performed in a et al., 2002), basal FSH (Muasher et al., 1988; Scott et al., limited number of relatively young women (Schipper et al., 1990; Bancsi et al., 2000), inhibin B (Seifer et al., 1997; 1998) or have compared small groups of relatively aged ã European Society of Human Reproduction and Embryology Antral follicle number re¯ects reproductive age Table I. Median values and ranges of endocrine and sonographic characteristics in the three age categories aMedian values of the old age group differed signi®cantly from the young age group.
bMedian values of the middle age group differed signi®cantly from the young age group.
cMedian values of the old age group differed signi®cantly from the middle age group.
Range values are given in parentheses.
women with very young controls (Klein et al., 1996a,b). It perpendicular measurements depending on the diameter (`6 or >6 therefore seems warranted to evaluate the aforementioned mm). The volume of each follicle was calculated by applying the sonographic and hormonal test parameters in a large group of equation of the volume of an ellipsoid (LQWQDQp/6). By adding all normal women of different ages with proven natural fertility.
volumes of follicles up to 10 mm in size in both ovaries, the total Since such women are likely to represent the age-related follicular volume was obtained (Haning et al., 1982). Mean follicular decline of the reproductive potential in the normal population, volume was calculated by dividing the total follicular volume by the number of follicles counted. The volume of the left and right ovary the assumption that their chronological age approximates was assessed by measuring the diameter of the ovarian contour in three reproductive age seems justi®ed. Chronological age, therefore, perpendicular directions and applying the equation for the volume of was used as the outcome variable to identify, ®rst, those factors an ellipsoid (D1QD2QD3Qp/6) to calculate ovarian volume. Total that show the best correlation with age, second, to obtain ovarian volume was then obtained by summing the volume of the left insight into how the various predictive parameters correlate and right ovary. Intra- and inter-observer variations of the antral with one another, and third, whether or not one or more follicle count and ovarian volume assessment have been published variables would improve the predictive performance of the best Endocrine testingBlood sampling was performed on the same day as the sonography examination. Hormone concentrations were measured in plasma (E2 This study was approved by the local Ethics Committee and written and FSH) and serum (inhibin B). Specimens were stored at ±20°C until informed consent was obtained from all participants. Healthy female processing. A random subgroup of 40 women underwent a GnRH volunteers (n = 162, age range 25±46 years) were recruited by agonist stimulation test in the cycle subsequent to the one in which the advertisement in the local newspapers. Women were enrolled in the basal endocrine and ultrasound characteristics were measured. A study protocol if they met all of the following criteria: (i) regular single s.c. injection of 100 mg of triptorelin (Decapeptyl; Ferring, menstrual cycles varying from 21 to 35 days, (ii) a biphasic body Hoofddorp, The Netherlands) was administered at day 3 of the cycle temperature chart, (iii) proven natural fertility by having had at least (Ranieri et al., 1998). Blood samples were taken immediately before one pregnancy carried to term, (iv) each of their pregnancies arisen and 24 h after GnRH agonist administration. The administered dose is spontaneously within 1 year after the start of unprotected intercourse, assumed to provide maximal stimulation of the pituitary with mean (v) no evidence of endocrinological disease, (vi) no history of ovarian peak levels of 52 IU/l for LH and 25 IU/l for FSH at 4 h after the surgery, (vii) no ovarian abnormalities as assessed by transvaginal injection and LH levels of 12.0 IU/l and FSH levels of 10.3 IU/l after ultrasound and (viii) hormonal contraception stopped b2 months 24 h (Broekmans et al., 1993). E2 concentrations were assayed with a before entering the study protocol. For study participation the microparticle enzyme immunoassay (MEIA) purchased from Abbott volunteers received monetary compensation.
Laboratories (Abbott Park, IL, USA) and using a semi-automated IMx analyser. Between-run coef®cients of variation (CV) for E2 were 10.1, 7.0 and 6.9% at 533, 1354 and 4197 pmol/l respectively (n = 49, 49 Transvaginal sonography of the ovaries was carried out on cycle day and 30). Concentrations of FSH were measured with the use of the 1, 2, 3 or 4. All sonography measurements were performed by the MEIA technology on a fully automated AxSYM immunoanalyser same observer (G.S.) using the 7.5 MHz transvaginal probe on a (Abbott Laboratories) according to the manufacturer's instructions.
Toshiba Capasee SSA-220A (Toshiba Medical Systems Europe BV, All specimens of each volunteer were analysed in the same run. The Zoetermeer, The Netherlands). Examination of the ovary was standard of the FSH assay was referenced against the World Health established by scanning from the outer to the inner margin (Pache Organization Second International Reference Preparation for human et al., 1990; van Santbrink et al., 1995). All follicles 2±10 mm in size FSH (78/549). The between-run CV of the FSH assay was 6.0, 6.6 and were measured and counted in each ovary. The sum of both counts was 8% at levels of 5.0, 25 and 75 IU/l (n = 46). Inhibin B levels were the antral follicle count. Follicle size was calculated from two or three measured using an immuno-enzymometric assay (Serotec, Oxford, Table II. Correlation matrix of basal endocrine and ultrasound parameters. (Total group, n = 162) Smallest ovary volume (small) ±0.24* ±0.10 Total follicular volume (TFV) ±0.36* ±0.17* 0.40* 0.69* 0.47* 0.42* 0.44* 0.25* 0.29* ±0.12 ±0.68* ±0.30* ±0.26* ±0.21* ±0.34* 0.37* were determined in a stepwise fashion after controlling for the effect of variables having the strongest correlation with chronological age in previous steps. The square of the correlation of a variable with chronological age was calculated as a re¯ection of the fraction of variation of chronological age explained by this variable and was considered a direct measure of its predictive performance. The additional predictive effect of the subsequent variables, after the best one had been selected, was calculated by multiplying the squares of the partial correlations with the remaining unexplained fraction.
For all statistical analyses, P < 0.05 was considered as signi®cant.
Figure 1. Dendrogram based on agglomerative cluster analysis. The Median values and ranges of the various endocrine and correlation between variables can be estimated from this ®gure by sonographic parameters for the three age groups are given in looking for the vertical line that connects the branches. For Table I. Values of all variables in the old age group differ example, the correlation between total ovarian volume and volume of largest ovary is ~0.95. TOV = total ovarian volume; TFV = total signi®cantly from those of the young group (except inhibin B) follicular volume; AFC = no. of follicles; InhB = inhibin B; and from those of the middle group (except E2, inhibin B and E2 = estradiol; MFV = mean follicular volume.
FSH). The number of follicles is the only variable for which values in the middle age group also signi®cantly differ from those of young women. Both the numbers of antral follicles and UK) (Groome et al., 1996). Intra- and inter-assay CV for the inhibin B assay were <14.6 and <14.0% respectively.
the total follicular volume decrease with increasing age.
However, the decrease of total follicular volume is less steep than that of the follicle number, while the mean volume per Statistical analysis was performed by using SPSS (Statistical Package follicle increases as a woman grows older and almost doubles for Social Sciences) for Windows (release 6.1.3) and GLIM in the old age group as compared with the young age group.
(Generalized Linear Interactive Modelling; NAG, Oxford, UK). For The correlation matrix (Table II) should be interpreted in the study group as a whole, three age groups were distinguished: a conjunction with Figure 1. Volumes of the smallest, the largest young group of women aged <35 years, an old group of women aged and both ovaries are highly correlated, indicating that they will >40 years and a middle group of women with ages in between.
provide almost the same information. Therefore, in subsequent Responses of inhibin B and E2 in the GAST group were de®ned as the analyses only one of themÐtotal ovarian volumeÐis taken serum or plasma level 24 h after GnRH agonist (cycle day 4 value) into account. The correlation between follicle number and total minus the baseline level before GnRH agonist was injected (cycle day follicular volume is also strong (r = 0.69), while the mean 3 value). Comparison between subgroup variables was performed by volume per antral follicle increases with age (r = 0.37). The the Mann±Whitney U-test or the Wilcoxon signed rank test, when sonographic variables, except mean follicular volume, together appropriate. The correlations between age, the various endocrine and form one cluster, in which correlation between the ovarian the sonographic parameters in the total group as well as in the GAST volume cluster and the follicle cluster is between 0.4 and 0.5 group were presented as a correlation matrix. In addition, in the total group an agglomerative cluster analysis on the absolute values of the (Figure 1). The interrelationship between the endocrinological correlations was performed, in order to visualize the strength of parameters is less clear-cut. One cluster is formed by inhibin B correlations between two variables, and to obtain better insight into and FSH, con®rming their rather strong and inverse correlation (r = ±0.40). E2 and mean follicular volume also form one, Using linear regression, univariate correlations of all variables with positively correlated cluster, which is in line with the positive chronological ageÐthe outcome variable in this studyÐwere correlation of both E2 and mean follicular volume with age calculated for the total group. Subsequently, partial correlations Antral follicle number re¯ects reproductive age Table III. Correlations of the endocrine and sonographic variables with Table IV. Baseline levels, stimulated levels and responses for inhibin B chronological age. (Total group, n = 162) and estradiol in the exogenous GnRH agonist administration group (n = 40) Estradiol (pmol/l) 187 (51±462) 536 (9±1163) 276 (±11±994) 0.001 aWilcoxon signed rank test, baseline versus stimulated levels.
Step 1: univariate correlations; step 2: partial correlations controlling for the for basal inhibin B. Moreover, E2 and inhibin B responses are number of follicles; step 3: partial correlations controlling for the number of clearly better correlated with antral follicle number (r = 0.75 follicles and total follicular volume.
and 0.73 respectively) than with age (r = ±0.42 and ±0.44 respectively). Finally, E2 and inhibin B responses are The results of the univariate and partial correlations of the endocrine and sonographic variables with age are shown in Table III. Number of follicles shows the best correlation with age (r = ±0.68). In contrast, the correlation of inhibin B with In this study we showed that the number of antral follicles age was weak and did not reach statistical signi®cance. The 2±10 mm in diameter, as measured by vaginal sonography correlations of the remaining variables were all highly during the early follicular phase, appeared to have the best signi®cant (P < 0.001). Only E2, total follicular volume and correlation with chronological age in a carefully selected group mean follicular volume appeared to have a statistically of women who had regular cycles and proven normal fertility.
signi®cant correlation with age which was independent from In such women the age-dependent changes of ovarian function the number of antral follicles (step 2). After controlling for are likely to re¯ect the physiological decline of female both number of follicles and total follicular volume, E2 fecundity. Hence, their chronological age can be assumed to continued to have a signi®cant, independent correlation with be a better approximation of reproductive age than that of age (step 3). Other partial correlations lost statistical signi®- women who suffer from infertility which may be associated cance in the next step (results not shown). The variation in with accelerated reproductive ageing. We realize, however, chronological age is explained for 46% by the best predictive that such an approximation is not perfect, because also in variable, the number of follicles. When adding the two normal fertile women of the same chronological age, variations independent predictive variables in a stepwise fashion, the in reproductive status may be present. However, we are not explained variation rose ®rst by 3% after the selection of total aware of a better `gold standard' for the process of reproductive follicular volume and by another 2% after the selection of E2.
The total explained variation thus increased from 46 to 51%.
It is generally accepted that reproductive ageing is directly Values of age and the basal endocrine and ultrasound related to the remains of the stock of primordial follicles, which variables studied in the GAST group did not differ from those is established during fetal life. This pool progressively empties in the remaining group (data not shown). Baseline levels, levels as a woman grows older and is (almost) completely exhausted after GnRH agonist stimulation and the corresponding when menopause is reached (Faddy et al., 1992). In a previous responses of inhibin B and E2 in the GAST group are shown study we showed that the pattern of age-dependent loss of in Table IV. The rise in hormone levels after the GnRH agonist antral follicle numbers is strikingly similar to that of the stimulation was statistically signi®cant for both hormones.
primordial follicle pool (Scheffer et al., 1999). It seems Correlations of age and the investigated hormones and plausible, therefore, that the number of antral follicles, as hormonal responses as well as the ultrasound variables are assessed by sonography, re¯ects what is left of the primordial shown in the correlation matrix (Table V). Note that the follicle pool and, thus, the reproductive age of an individual correlations among age and the endocrine and ultrasound baseline variables are in the same order as for the total group The number of antral follicles correlated much better with (Table II), with the exception that the correlation for inhibin B the age of the women evaluated in this study, than other with antral follicle count seems more favourable, presumably presumed basal markers for reproductive age, including FSH, due to chance variation. The weak or statistically non- inhibin B, E2 and ovarian volume. As expected, total follicular signi®cant correlations for baseline levels of inhibin B and volume appeared to be a simple derivative from number of E2 with age are changed into more robust and signi®cant follicles, evidenced by a strong and positive correlation with correlations when the response in the GnRH agonist test is numbers of follicles (r = 0.69) and a negative correlation with considered (Tables II and IV). Baseline levels of inhibin B reproductive age (r = ±0.34). We were surprised, however, to show a statistically signi®cant correlation with antral follicle ®nd that the mean follicular volume considerably increased numbers. However, the correlations with the number of antral with age and had almost doubled in the old age group in follicles of the E2 and inhibin B responses after GnRH agonist comparison with the young ones. The correlation of mean stimulation become highly signi®cant and clearly stronger than follicular volume, a derivative of the total follicular volume Table V. Correlation matrix of basal endocrinological and ultrasound parameters in the exogenous GnRH agonist administration (GAST) group (n = 40) and the number of follicles, with age, therefore, is positive (r = Although the number of antral follicles in both ovaries 0.37). E2 levels are also positively correlated with age.
appeared to have the best correlation with chronological age, Apparently, the few antral follicles which are still present in basal E2 and total follicular volume slightly improved the the early follicular phase in older aged women, are not only prediction already obtained with the antral follicle count.
larger but also produce more E2 than the many, but smaller, Apparently, the predictive information provided by FSH, antral follicles present at a younger age. Several studies have inhibin B and total ovarian volume is already covered by the shown that the follicular phase of the menstrual cycle in older number of follicles. Nevertheless, 90% of the explained aged women becomes considerably shorter (Lenton et al., variance of age is already obtained with the number of follicles 1984; Klein et al., 1996a; van Zonneveld et al., 2003). This alone, while the additional contributions of total follicular phenomenon has been postulated as suggesting accelerated volume and E2 are 6 and 4% respectively. Such an improve- growth of antral follicles in older women (Klein et al., 1996a).
ment in predictive performance seems almost negligible.
Since the diameter on the day of ovulation and the mean Therefore, the use of antral follicle counts as a single test to follicular growth per day were almost the same in older and predict the response to controlled ovarian stimulation and the younger women (van Zonneveld et al., 2003), we suggest that probability of pregnancy in assisted reproduction seems follicular development in older women is not accelerated but rational. Several studies have analysed the usefulness of antral advanced. Dominant follicle growth in older women is likely to follicle counts in this respect. In a study of IVF patients (Tomas have started already in the luteal phase of the previous cycle et al., 1997) it was shown that the ovarian responsiveness is before menstruation starts. This earlier start of development is dependent on the number of small antral follicles (2±5 mm). In in accordance with data from the literature, indicating that the another study, patients with an antral follicle (2±8 mm) count intercycle FSH rise is not only higher, but also starts earlier in of less than four appeared to have a signi®cantly higher rate of older women (Klein et al., 1996a; van Zonneveld et al., 2003).
cancellation due to poor response and no pregnancies occurred Advanced development of follicular growth fully explains why in this group of patients (Chang et al., 1998). In several studies, at the onset of the menstrual cycle, antral follicles are larger logistic regression analysis has shown that the number of antral and, though lower in number, produce higher E2 levels in older follicles is a signi®cant predictor for the occurrence of poor ovarian response in IVF with an adequate balance between test While numbers of follicles already have clearly decreased in sensitivity and speci®city (Frattarelli et al., 2000; Pohl et al., the middle-aged, hormone levels of FSH, E2 and inhibin B only 2000; Dumesic et al., 2001; Hsieh et al., 2001; Huang et al., become notably changed in women aged >40 years.
2001; Bancsi et al., 2002). Most studies, however, also Apparently, age-dependent hormonal changes are a relatively revealed that pregnancy prediction from antral follicle counts, late phenomenon and only occur when follicle numbers are even in combination with other ovarian reserve factors, greatly reduced (te Velde and Pearson, 2002). This conclusion is in line with the results of several studies in normal It was shown that after the administration of a high dose of volunteers. Neither maximum FSH and inhibin B concentra- GnRH agonist, antral follicles greatly increase their production tions in the follicular phase nor cycle day 3 FSH levels were and release of E2 and inhibin B from the granulosa cells within correlated with age in normally cycling, female volunteers 24 h. This ®nding is not new for E2 (Winslow et al., 1991; aged 20±35 years (Schipper et al., 1998). A study in young Ranieri et al., 1998) and con®rms results from other studies controls (aged 20±25 years) and reproductively aged women (Avrech et al., 1996; Galtier-Dereure et al., 1996; Ravhon et al., (aged 40±45 years) showed that inhibin B serum levels were 2000). As E2 and inhibin B are produced from small antral only signi®cantly lower in the reproductively aged women at follicles present in the early follicular phase of the cycle, basal the day of maximal FSH (Klein et al., 1996a). Finally, lower levels would re¯ect the size of the FSH sensitive cohort of early follicular inhibin B serum levels were only found in older follicles. Although this may be true for inhibin B, E2 release is cycling women compared with young controls (Welt et al., much more dependent on other sources such as the remnants of 1999). All this explains why the correlations of basal FSH, E2 the corpus luteum or an advanced growing follicle. Once and inhibin B with chronological age are only weak to stimulated by an endogenous FSH (and LH) rise in the GAST, the relation between inhibin B and the cohort size becomes Antral follicle number re¯ects reproductive age magni®ed as evidenced by the improved correlation with the Dumesic, D.A., Damario, M.A., Session, D.R., Famuyide, A., Lesnick, T.G., Thornhill, A.R. and McNeilly, A.S. (2001) Ovarian morphology and serum hormone markers as predictors of ovarian follicle recruitment by clear positive correlation with antral follicle number shows that gonadotropins for in vitro fertilization. J. Clin. Endocrinol. Metab., 86, the cohort as a whole contributes to the peripheral E These ®ndings also con®rm studies in which the instant E Dzik, A., Lambert-Messerlian, G., Izzo, V.M., Soares, J.B., Pinotti, J.A. and inhibin B response to a single FSH dose administration Seifer, D.B. (2000) Inhibin B response to EFORT is associated with the outcome of oocyte retrieval in the subsequent in vitro fertilization cycle.
appeared clearly related to the number of stimulated follicles in ovarian hyperstimulation for IVF (Fanchin et al., 1994; Dzik Eldar-Geva, T., Robertson, D.M., Cahir, N., Groome, N., Gabbe, M.P., et al., 2000; Eldar-Geva et al., 2000; Elting et al., 2001).
Maclachlan, V. and Healy, D.L. (2000) Relationship between serum inhibin A and B and ovarian follicle development after a daily ®xed dose Moreover, the responses of E2 and inhibin B in the GAST are administration of recombinant follicle-stimulating hormone. J. Clin.
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and at the same time is highly correlated with the E Evers, J.L., Slaats, P., Land, J.A., Dumoulin, J.C. and Dunselman, G.A. (1998) inhibin B response in the GAST, the question arises whether Elevated levels of basal estradiol-17beta predict poor response in patients the GAST may be a superior test in the prediction of outcome with normal basal levels of follicle-stimulating hormone undergoing in vitro in assisted reproduction treatment. Back-to-back comparison fertilization. Fertil. Steril., 69, 1010±1014.
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