J. van Disseldorp

Comparison of inter- and intra-cycle variability of anti-Müllerian hormone and antral follicle counts

BACKGROUND The antral follicle count (AFC) and anti-Müllerian hormone (AMH) both represent age-related follicular decline quite accurately, although long-term follow-up studies are still lacking. The best ovarian reserve test would need only a single, cycle-independent measurement to be representative. METHODS To compare the inter- and intra-cycle stability of AFC and AMH, we used age-adjusted intra-class correlation coefficients (ICCs). To measure inter-cycle stability across a number of up to four menstrual cycles, we used data, prospectively collected for the purpose of an other study, from 77 regularly cycling, infertile women aged 24-40 years. AMH and AFC values were measured on cycle day 3. To study intra-cycle variability, we used data from a prospective cohort study of 44 regularly cycling volunteers, aged 25-46 years and measured AMH and assessed the AFC (2-10 mm) every 1-3 cycle days. RESULTS Between menstrual cycles, AFC and AMH varied between 0 and 25 follicles (median 10), and 0.3 and 27.1 ng/ml (median 4.64). The difference in age-adjusted ICC between AMH [ICC, 0.89 (95% CI, 0.84-0.94)] and AFC [ICC, 0.71 (95% CI, 0.63-0.77)] was 0.18 (95% CI, 0.12-0.27). For the intra-cycle variation, 0-43 antral follicles (median 7) were counted per volunteer. The difference in age-adjusted ICC between AMH [ICC, 0.87 (95% CI, 0.82-0.91)] and AFC [ICC, 0.69 (95% CI, 0.46-0.82)] was 0.18 (95% CI, 0.034-0.42). CONCLUSIONS Serum AMH demonstrated less individual intra- and inter-cycle variation than AFCs and may therefore be considered a more reliable and robust means of assessing ovarian reserve in subfertile women.

Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach

BACKGROUND Although ovarian reserve tests (ORTs) are frequently used prior to IVF treatment for outcome prediction, their added predictive value is unclear. We assessed the added value of ORTs to patient characteristics in the prediction of IVF outcome. METHODS An individual patient data (IPD) meta-analysis from published studies was performed. Studies on FSH, anti-Müllerian hormone (AMH) or antral follicle count (AFC) in women undergoing IVF were identified and authors were contacted. Using random intercept logistic regression models, we estimated the added predictive value of ORTs for poor response and ongoing pregnancy after IVF, relative to patient characteristics. RESULTS We were able to collect 28 study databases, comprising 5705 women undergoing IVF. The area under the receiver-operating characteristic curve (AUC) for female age in predicting poor response was 0.61. AFC and AMH each significantly improved the model fit (P-value <0.001). Moreover, almost a similar accuracy was reached using AMH or AFC alone (AUC 0.78 and 0.76, respectively). Combining the two tests, however, did not improve prediction (AUC 0.80, P = 0.19) of poor response. In predicting ongoing pregnancy after IVF, age was the best single predictor (AUC 0.57), and none of the ORTs added any value. CONCLUSIONS This IPD meta-analysis demonstrates that AFC and AMH clearly add to age in predicting poor response. As single tests, AFC and AMH both fully cover the prediction of poor ovarian response. In contrast, none of the ORTs add any information to the limited capacity of female age to predict ongoing pregnancy after IVF. The clinical usefulness of ORTs prior to IVF will be limited to the prediction of ovarian response.

Prevalence of unsuspected uterine cavity abnormalities diagnosed by office hysteroscopy prior to in vitro fertilization

BACKGROUND Whether implantation occurs after in vitro fertilization (IVF) depends on the embryo, uterine receptivity or a combination of both. The prevalence of minor intrauterine abnormalities identified at hysteroscopy in cases with a normal transvaginal sonography (TVS) has been recorded to be as high as 20-40%. Diagnosing and treating such pathology prior to initiating IVF/intra-cytoplasmic sperm injection (ICSI), has been widely advocated without high-quality evidence of a beneficial effect. The objective of the current study was to assess, by screening office hysteroscopy, the prevalence of unsuspected intrauterine abnormalities in an asymptomatic population of IVF patients, in whom TVS had not revealed any pathology. METHODS The prevalence of unsuspected intrauterine abnormalities in patients allocated for a randomized controlled trial was prospectively assessed at two tertiary infertility care units: Academic Hospital at the Dutch-speaking Brussels Free University and University Medical Center Utrecht. A total of 678 unselected, asymptomatic, infertile women with a regular indication for a first IVF/ICSI treatment underwent office hysteroscopy. Only asymptomatic patients, aged < or = 42 years, with a normal TVS and no previous hysteroscopy were included. The presence of predefined intrauterine abnormalities was recorded and described in a standardized manner. RESULTS Endometrial polyps were identified in 41 (6%) women and submucous myomas in 6 women (1%). Some women were also diagnosed with intrauterine adhesions (2%) or septa (2%). The overall prevalence of any predefined intrauterine abnormality in this IVF/ICSI population was 11%. CONCLUSIONS The observed prevalence of unsuspected intrauterine abnormalities in asymptomatic patients indicated for their first IVF/ICSI treatment appeared to be clearly lower than previously reported (11 versus 20-45%). This may have implications for the significance of these abnormalities regarding prospects in IVF/ICSI treatment cycles.

The Relationship Between Anti-Müllerian Hormone in Women Receiving Fertility Assessments and Age at Menopause in Subfertile Women: Evidence From Large Population Studies

CONTEXT Anti-Müllerian hormone (AMH) concentration reflects ovarian aging and is argued to be a useful predictor of age at menopause (AMP). It is hypothesized that AMH falling below a critical threshold corresponds to follicle depletion, which results in menopause. With this threshold, theoretical predictions of AMP can be made. Comparisons of such predictions with observed AMP from population studies support the role for AMH as a forecaster of menopause. OBJECTIVE The objective of the study was to investigate whether previous relationships between AMH and AMP are valid using a much larger data set. SETTING AMH was measured in 27 563 women attending fertility clinics. STUDY DESIGN From these data a model of age-related AMH change was constructed using a robust regression analysis. Data on AMP from subfertile women were obtained from the population-based Prospect-European Prospective Investigation into Cancer and Nutrition (Prospect-EPIC) cohort (n = 2249). By constructing a probability distribution of age at which AMH falls below a critical threshold and fitting this to Prospect-EPIC menopausal age data using maximum likelihood, such a threshold was estimated. MAIN OUTCOME The main outcome was conformity between observed and predicted AMP. RESULTS To get a distribution of AMH-predicted AMP that fit the Prospect-EPIC data, we found the critical AMH threshold should vary among women in such a way that women with low age-specific AMH would have lower thresholds, whereas women with high age-specific AMH would have higher thresholds (mean 0.075 ng/mL; interquartile range 0.038-0.15 ng/mL). Such a varying AMH threshold for menopause is a novel and biologically plausible finding. AMH became undetectable (<0.2 ng/mL) approximately 5 years before the occurrence of menopause, in line with a previous report. CONCLUSIONS The conformity of the observed and predicted distributions of AMP supports the hypothesis that declining population averages of AMH are associated with menopause, making AMH an excellent candidate biomarker for AMP prediction. Further research will help establish the accuracy of AMH levels to predict AMP within individuals.

Predicting menopausal age with anti-Müllerian hormone: a cross-validation study of two existing models

Abstract Objective This study aimed to cross-validate two comparable Weibull models of prediction of age at natural menopause from two cohorts, the Scheffer, van Rooij, de Vet (SRV) cohort and the Tehran Lipid and Glucose Study (TLGS) cohort. It summarizes advantages and disadvantages of the models and underlines the need for achieving correct time dependency in dynamic variables like anti-Müllerian hormone. Methods Models were fitted in the original datasets and then applied to the cross-validation datasets. The discriminatory capacity of each model was assessed by calculating C-statistics for the models in their own data and in the cross-validation data. Calibration of the models on the cross-validation data was assessed by measuring the slope, intercept and Weibull shape parameter. Results The C-statistic for the SRV model on the SRV data was 0.7 (95% confidence interval (CI) 0.7–0.8) and on the TLGS data it was 0.8 (95% CI 0.8–0.9). For the TLGS model on the TLGS data, it was 0.9 (95% CI 0.8–0.9) and on the SRV data it was 0.7 (95% CI 0.6–0.8). After calibration of the SRV model on the TLGS data, the slope was 1, the intercept -0.3 and the shape parameter 1.1. The TLGS model on the SRV data had a slope of 0.3, an intercept of 12.7 and a shape parameter of 0.6. Conclusions Both models discriminate well between women that enter menopause early or late during follow-up. While the SRV model showed good agreement between the predicted risk of entering menopause and the observed proportion of women who entered menopause during follow-up (calibration) in the cross-validation dataset, the TLGS model showed poor calibration.

Relationship of Serum Antimüllerian Hormone Concentration to Age at Menopause

Antimullerian hormone (AMH), also known as mullerian inhibiting substance (MIS), is viewed as a quantitative marker of ovarian reserve. Serum AMH levels are readily measured and independent of the menstrual cycle, and they correlate closely with antral follicle counts. Unlike follicle counts, however, AMH has not been evaluated as a predictor of reproductive status. The investigators measured AMH levels in 144 normal, fertile women and assessed their correlation with age at menopause. Data on the onset of menopause were taken from a population-based cohort study, the Prospect-European Prospective Investigation into Cancer and Nutrition. The maximum likelihood approach was used to estimate an AMH threshold for predicting menopause. Predictions of age at menopause were derived from an individual womans AMH relative to percentiles of the distribution of AMH for a given age and the corresponding percentiles of the predictive distribution of age at menopause. Good conformity was observed between the observed distribution of age at menopause and that predicted from decreasing AMH levels. A woman with a low AMH for her age is likely to enter menopause at a younger age, between ages 41 and 44 years or 7 to 10 years before the median age of 51 years that would be expected without knowing the AMH level. A woman with a high AMH for her age can expect to become menopausal at a later age, between 51 and 53 years or up to 2 years after the median age. These findings suggest that AMH reflects reproductive age more realistically than does chronologic age alone. The similarity between observed and predicted distributions of age at menopause supports the view that AMH levels are related to the onset of menopause.