1 Department of Obstetrics and Gynaecology and 2 Clinical Trial Centre, The University of Hong Kong, Hong Kong Special Administrative Region, Peoples Republic of China
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. e-mail: nghye{at}hkucc.hku.hk
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Abstract |
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Key words: AFC/age/Chinese women/Doppler/ovarian reserve
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Introduction |
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A number of parameters known as ovarian reserve markers have been examined in many assisted reproduction technology (ART) programmes to predict ovarian responses prior to ovarian stimulation with gonadotrophin. Hormonal markers include basal FSH (Scott and Hofmann et al., 1995; Sharara et al., 1998
) and inhibin B (Seifer et al., 1997
, 1999
; Tinkanen et al., 1999
; Dzik et al., 2000
) levels. Other less commonly used hormonal markers such as serum estradiol level (Licciardi et al., 1995
), FSH/LH ratio (Mukherjee et al., 1996
), GnRH agonist stimulation test (Padilla et al., 1990
) and exogenous FSH ovarian reserve test (Fanchin et al., 1994
) are of limited value in the prediction of ovarian response (Bukman and Heineman, 2001
). Recently, ultrasound assessment of the ovarian volume (Syrop et al., 1995
; Lass et al., 1997
; Syrop et al., 1999
), total antral follicle count (AFC) (Tomás et al., 1997
); Chang et al., 1998a
,b; Frattarelli et al., 2000
; Ng et al., 2000
; Hsieh et al., 2001
; Nahum et al., 2001
) and ovarian stromal blood flow (Zaidi et al., 1996
; Engmann et al., 1999
; Kupesic and Kurjak, 2002
; Kupesic et al., 2003
; Popovic-Todorovic et al., 2003
) were also found to be useful in predicting ovarian responses.
Many women in developed countries delay childbearing to fulfil their personal commitments. An accurate assessment of reproductive age would be of help in counselling these women about their fertility potential and perhaps in scheduling pregnancies. The majority of ovarian reserve tests are performed in women presenting with infertility problems. To generalize data from infertile patients to fertile subjects seems inappropriate as infertile patients may have a more advanced reproductive age, which will contribute to their infertility problem. There are very few studies addressing the effects of age on these markers in women with proven fertility, especially in Asia. This prospective study was intended to evaluate the effect of age on hormonal and ultrasound markers and to correlate the ultrasound markers with the hormonal parameters in Chinese women with proven fertility.
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Materials and methods |
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Two to three months after termination of pregnancy or sterilization, they attended the Day Care Centre for a transvaginal ultrasound examination and blood test in the early follicular phase (days 24) of their period. All ultrasound examinations were carried out by E.H.Y.N. at 810 a.m. using a 6.5 MHz vaginal probe (Aloka, Model SSD-5500, Aloka Co. Ltd, Tokyo, Japan) with the same ultrasound setting and without knowing the age of patients. The length, height and width of each ovary were measured in the sagittal and coronal planes during transvaginal scanning. Ovarian volume was then obtained using a formula for the volume of an ellipsoid, i.e.
/6 (length x height x width). The number of antral follicles <10 mm in each ovary was counted. The stromal blood flow of the ovary was assessed by colour Doppler ultrasound. Flow velocity waveforms were obtained from stromal blood vessels away from the ovarian capsule. The gate of the Doppler was positioned when the vessel with good colour signals was identified on the screen. The peak systolic velocity (PSV) of stromal vessels was calculated electronically when three similar, consecutive waveforms of good quality were obtained. Ovarian stromal blood flow was evaluated at three positions at random, and the one with the highest PSV was chosen. As no significant difference in PSV between the left and right side of ovarian stromal vessels was obtained, the mean value was used. The intra-observer coefficient of variation was 7% for AFC, 7% for ovarian volume and 16% for PSV.
Blood was then taken for the measurement of FSH and inhibin B levels. Serum FSH was measured by a two-site sandwich immunoassay (Bayer Corporation, Tarrytown, NY), and the inter- and intra-assay coefficients of variation were 2.8 and 1.7%, respectively. Serum inhibin B was measured by a two-site enzyme-linked immunoassay (Serotec, Kidlington, Oxford, UK), and the inter- and intra-assay coefficients of variation were <7%.
Statistical analysis
Women aged 20, 2130, 3140 and >40 years were classified as groups IIV, respectively. The outcome measures were FSH level, inhibin B level, mean ovarian volume (averaged volume of both ovaries) and total ovarian volume (volume of both ovaries), AFC (antral follicle number of both ovaries) and mean PSV of ovarian stromal blood vessels. Continuous variables were not normally distributed and are given as the median (2.5th97.5th centiles), unless indicated. Statistical tests were carried out by KruskalWallis and MannWhitney U-tests, where appropriate. Correlation was assessed by the Spearman rank method. A P-value (two-tailed) of <0.05 was taken as significant.
The effect of age on AFC was examined by both conventional linear regression and biphasic linear regression models, with and without a logarithmic transformation of AFC. A biphasic linear regression was fitted to the data with all parameters including the breakpoint estimated by the least squares estimates. The 95% confidence interval (CI) for the breakpoint was obtained by parametric bootstrap of size 1000 (Davison and Hinkley, 1997). The difference between these two models was examined by an F-test. The estimation was programmed in the Statistical Analysis System (SAS, SAS Institute Inc., Cary, NC) Version 8.2.
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Results |
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Discussion |
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The significance of AFC has been evaluated extensively in infertile patients undergoing ART treatment. Tomás et al. (1997) first concluded that AFC before ovarian stimulation was a better predictor of the ovarian response than the ovarian volume or age alone. Chang et al. (1998a
) found a highly significant correlation between AFC and the number of oocytes, and a higher chance of cycle cancellation, lower estradiol level and higher gonadotrophin dosage in cycles with antral follicle number
3. We demonstrated that AFC achieved the best predictive value, followed by basal FSH, body mass index and age of women, in a prospective study of 128 women undergoing the first IVF cycle using a standard regimen of ovarian stimulation (Ng et al., 2000
). Other studies (Frattarelli et al., 2000
; Hsieh et al., 2001
; Nahum et al., 2001
; Kupesic and Kurjak, 2002
; Popovic-Todorovic et al., 2003
) also confirm the importance of AFC in the prediction of ovarian response.
There is little information in the literature regarding the effect of age on AFC in fertile women. In 31 healthy Caucasian volunteers, AFC decreased by 0.95 follicles per year of age or 60% between 22 and 42 years (Reuss et al., 1996
). A more recent study (Scheffer et al., 1999
) of 162 fertile women in The Netherlands demonstrated that AFC was best correlated with age and declined by 8.2% per year (95% CI 5.211.2%) in a linear regression model. Our study revealed that the decline of AFC in fertile Chinese women was only 3.8% per year (95% CI 2.74.9%) or 0.35 follicles per year (95% CI 0.260.45). Our decline rate was similar to 0.47 follicles per year in infertile Chinese women undergoing ovarian stimulation and artificial insemination in Taiwan (Chang et al., 1998b
), but was much lower than those reported in Caucasians (Reuss et al., 1996
; Scheffer et al., 1999
). This may be a real difference, and further studies are warranted to investigate the reasons for the ethnic difference in AFC decline. Different AFC decline rates may explain variations in pregnancy rate between populations in studies of the efficacy of intrauterine contraceptive devices (UNDP/UNFPA/WHO, 1997
) and of women with lactational amenorrhoea (World Health Organization Task Force on Methods for the Natural Regulation of Fertility, 1999
).
Moreover, Scheffer et al. (1999) indicated a biphasic pattern of AFC decline in their population, as AFC declined by 4.8% per year before the age of 37 years compared with 11.7% thereafter. In this study, the conventional linear model gave the best fit to the data and was not improved by the biphasic linear regression model. A linear decline was also found by Reuss et al. (1996
) and Chang et al. (1998b
). When the biphasic linear regression model was applied, the breakpoint was at 29.1 years with a large 95% CI, reflecting a large variation of AFC in the same age group, especially in the older age group. The observation of Scheffer et al. (1999
) is concordant with the widely accepted biphasic model of follicle disappearance from birth to menopause based on autopsy findings and histological analyses of ovaries (Faddy and Gosden, 1995
). This bi-exponential model suggests that the total follicle number declines bi-exponentially with age and the loss of follicles accelerates around the age of 3738 years. This model, however, has been questioned by re-examination of raw data with different statistical models, and there may not be any abrupt increase in the rate of follicular atresia after the age of 38 years (Leidy et al., 1998
). Moreover, AFC shown on scanning may not truly reflect the follicle pool present in the ovaries, and the follicular dynamics from the primordial stage to the antral stage are poorly understood (McGee and Hsueh, 2000
).
Ovarian volume in terms of total ovarian volume, volume of the smallest ovary and mean ovarian volume has also been evaluated to predict ovarian responses during ART treatment (Syrop et al., 1995, 1999
; Lass et al., 1997
) and was a better measure than basal FSH level (Syrop et al., 1999
). There was a significant negative correlation between age of infertile women and ovarian volume shown by two-dimensional (Lass et al., 1997
) and by three-dimensional (Kupesic et al., 2003
) ultrasound, but Syrop et al. (1995
) and Sharara and Mcclamrock (1999
) could not demonstrate such a correlation. Christensen et al. (1997
) revealed that the ovarian volume was not related to age in 428 healthy women aged 1445 years attending a family planning clinic, but a linear relationship existed between menopause age and ovarian volume (Tepper et al., 1995
). Our study found a moderate negative correlation of age with ovarian volume, similar to that of Scheffer et al. (1999
). These data suggest that there are no major changes in ovarian volume during reproductive ages until the peri-menopausal period.
Ovarian stromal blood flow can be evaluated by colour Doppler ultrasound and power Doppler. The ovarian response during ART was significantly correlated with mean PSV measured prior to pituitary downregulation (Zaidi et al., 1996) or after downregulation (Engmann et al., 1999
). Those with normal ovarian responses had significantly higher velocity than poor responders (10.2 ± 5.8 versus 5.2 ± 4.2 cm/s). Other Doppler flow indices were not useful. Our study could not find any effect of age on mean PSV determined by colour Doppler, and this may be related to the method of detection. Power Doppler imaging is more sensitive than colour Doppler imaging at detecting low velocity flow, and hence improves the visualization of small vessels (Guerriero et al., 1999
). Increasing age was associated with reduced ovarian stromal vascularity detected by three-dimensional power Doppler in general (Pan et al., 2002
) and in infertile patients (Kupesic et al., 2003
).
The early follicular phase FSH level taken prior to the treatment cycle is widely used in many ART programmes and is a better predictor of ovarian response than the age of women (Cahill et al., 1994; Sharif et al., 1998
). Although there was a positive correlation of age with serum FSH level shown in this study, the majority of the women had a normal range of FSH levels (<10 IU/l), even in women >40 years. Inhibin B level may be an earlier marker for ovarian reserve than FSH level as decreased inhibin B levels were found in women with reduced ovarian reserve before a rise in FSH levels (Seifer et al., 1999
). Seifer et al. (1997
), Tinkanen et al. (1999
) and Dzik et al. (2000
) reported that women with inhibin B levels <45 pg/ml demonstrated a poorer ovarian response during ART than women with levels
45 pg/ml, while others (Corson et al., 1999
; Hall et al., 1999
; Creus et al., 2000
) could not find any value in the prediction of ovarian response or pregnancy rate. Therefore, it is still a matter of controversy in the literature whether inhibin B is a useful marker for ovarian reserve. Our results could not show any significant correlation of age with serum inhibin B level. Inhibin B is secreted by granulosa cells of developing follicles and may reflect the number or quality of these developing follicles (Hall et al., 1999
). There was no significant correlation between inhibin B level and AFC in this study, which was different from the observation of Scheffer et al. (2003
). The reason for this discrepancy is unknown. Similar FSH and inhibin B levels across different age groups in this study support the concept that age-dependent hormonal changes are a relatively late phenomenon and only occur when the number of follicles is much reduced (te Velde and Pearson, 2002
). Hormonal levels following some sort of stimulation may be a better reflection of AFC, as the stimulated inhibin B level after a GnRH agonist was highly correlated with AFC (Scheffer et al., 2003
). Serum anti-Müllerian hormone, which is involved in control of primordial follicle recruitment in the mouse (Durlinger et al., 1999
), appears to be an early marker for ovarian reserve (Seifer et al., 2002
; Van Rooij et al., 2002
; Fanchin et al., 2003
).
In conclusion, AFC is the only ovarian reserve marker that was significantly different among the four age groups. AFC had the best correlation with age, followed by FSH level and ovarian volume. The decline of AFC over age was linear, at 3.8% per year (95% CI = 2.74.9%) or 0.35 follicles per year (95% CI = 0.260.45%).
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Acknowledgements |
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References |
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Submitted on May 12, 2003; accepted on June 19, 2003.