Back to the basics of ovarian aging: a population-based study on longitudinal anti-Müllerian hormone decline

Abstract

BackgroundAnti-Müllerian hormone (AMH) is currently used as an ovarian reserve marker for individualized fertility counseling, but very little is known of individual AMH decline in women. This study assessed whether the decline trajectory of AMH is uniform for all women, and whether baseline age-specific AMH levels remain consistently high or low during this trajectory.MethodsA total of 3326 female participants from the population-based Doetinchem Cohort Study were followed with five visits over a 20-year period. Baseline age was 40 ± 10 years with a range of 20–59 years.AMH was measured in 12,929 stored plasma samples using the picoAMH assay (AnshLabs). Decline trajectories of AMH were studied with both chronological age and reproductive age, i.e., time to menopause. Multivariable linear mixed effects models characterized the individual AMH decline trajectories.ResultsThe overall rate of AMH decline accelerated after 40 years of age. Mixed models with varying age-specific AMH levels and decline rates provided the significantly best fit to the data, indicating that the fall in AMH levels over time does not follow a fixed pattern for individual women. AMH levels remained consistent along individual trajectories of age, with an intraclass correlation coefficient (ICC) of 0.87. The ICC of 0.32 for AMH trajectories with time to menopause expressed the large variation in AMH levels at a given time before the menopause. The differences between low and high age-specific AMH levels remained distinguishable, but became increasingly smaller with increasing chronological and reproductive age.ConclusionsThis is the first study to characterize individual AMH decline over a long time period and broad age range. The varying AMH decline rates do not support the premise of a uniform AMH decline trajectory. Although age-specific AMH levels remain consistently high or low with increasing age, the converging trajectories and variance of AMH levels at a given time before menopause shed doubt on the added value of AMH to represent individualized reproductive age.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0699-y) contains supplementary material, which is available to authorized users.

Anti-Müllerian Hormone Trajectories Are Associated With Cardiovascular Disease in Women

“…First, we characterized decline trajectories of log AMH with the use of a linear mixed model analysis, taking into account varying AMH levels and decline rates between individuals by adding a random intercept and slope, respectively, for each individual (details previously described 20 ). In this way, a separate effect for an individual AMH level and slope at time point t could be modeled.…”

“…Menopausal status was assessed through information on current cycle regularity, date of the last menstrual period, and reproductive surgery (for a more detailed description, see our study on AMH trajectories 20 ). Current smoking status at each follow-up round was derived from the questionnaires, where participants were regarded as current smokers if they reported to smoke at least 1 cigarette per month.…”

“…The details of these measurements were previously described. 20 The plasma samples from round 1 were stored at -30°C, and the samples from rounds 2 to 5 were stored at -80°C. Before the current study, samples were thawed once for additional measurements and immediately refrozen.…”

“…Natural splines were added to the time variable to take into account the individual nonlinear decline of AMH. 20 Models were subsequently adjusted for the following time-varying covariates: current OC use, current smoking, menopausal status (pre-or postmenopausal based on cycle status), body mass index, diastolic blood pressure, total cholesterol, HDL-C, glucose, hormone therapy use, and use of blood pressure-or lipid-lowering medication. Diastolic blood pressure was chosen to represent blood pressure because it was normally distributed, whereas systolic blood pressure was slightly right-skewed, even after logarithmic transformation.…”

“…This process was performed by using the CG-LMS method (conjugate grading, lambda-mu-sigma), previously described by Dólleman and de Kat. 20,21 A model was made of the nonlinear distribution of AMH with standardization for age using smoothing splines for AMH and taking into account skewness, the median, and coefficient of variation. This fitted model was then applied to predict in which quartile the AMH level of a woman belonged given her age.…”