Human ovarian reserve from conception to the menopause

Abstract

The human ovary contains a fixed number of non-growing follicles (NGFs) established before birth that decline with increasing age culminating in the menopause at 50-51 years. The objective of this study is to model the age-related population of NGFs in the human ovary from conception to menopause. Data were taken from eight separate quantitative histological studies (n = 325) in which NGF populations at known ages from seven weeks post conception to 51 years (median 32 years) were calculated. The data set was fitted to 20 peak function models, with the results ranked by obtained r2 correlation coefficient. The highest ranked model was chosen. Our model matches the log-adjusted NGF population from conception to menopause to a five-parameter asymmetric double Gaussian cumulative (ADC) curve (r2 = 0.81). When restricted to ages up to 25 years, the ADC curve has r2 = 0.95. We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. Furthermore, we found that the rate of NGF recruitment towards maturation for most women increases from birth until approximately age 14 years then decreases towards the menopause. To our knowledge, this is the first model of ovarian reserve from conception to menopause. This model allows us to estimate the number of NGFs present in the ovary at any given age, suggests that 81% of the variance in NGF populations is due to age alone, and shows for the first time, to our knowledge, that the rate of NGF recruitment increases from birth to age 14 years then declines with age until menopause. An increased understanding of the dynamics of human ovarian reserve will provide a more scientific basis for fertility counselling for both healthy women and those who have survived gonadotoxic cancer treatments.

Figure 1. The model that best fits the histological data.

The best model for the establishment of the NGF population after conception, and the subsequent decline until age at menopause is described by an ADC model with parameters  = 5.56 (95% CI 5.38–5.74),  = 25.6 (95% CI 24.9–26.4),  = 52.7 (95% CI 51.1–54.2),  = 0.074 (95% CI 0.062–0.085), and  = 24.5 (95% CI 20.4–28.6). Our model has correlation coefficient  = 0.81, fit standard error = 0.46 and F-value = 364. The figure shows the dataset (n = 325), the model, the 95% prediction limits of the model, and the 95% confidence interval for the model. The horizontal axis denotes age in months up to birth at age zero, and age in years from birth to 51 years.

Figure 2. The model that best fits the histological data for ages up to 25 years.

The best model for the establishment of the NGF population after conception, and the subsequent decline until 25 years of age is described by an ADC model with parameters  = 5.79 (95% CI 5.03–6.55),  = 28.0 (95% CI 15.8–40.2),  = 57.4 (95% CI 33.1–81.8),  = 0.074 (95% CI 0.067–0.081), and  = 34.3 (95% CI −4.2–72.8). This model has correlation coefficient  = 0.95, fit standard error = 0.29 and F-value = 585. This figure shows the dataset (n = 126), the model, the 95% prediction limits of the model, and the 95% confidence interval for the model. The horizontal axis denotes age in months up to birth at age zero, and age in years from birth to 25 years.

Figure 3. The highest ranked model that allows growth after the initial peak.

The highest-ranked non-peak model returned by TableCurve is a polynomial given by . Compared to the ADC model for the same data, the model has lower correlation coefficient, higher fit standard error, and lower F-statistic. All other TableCurve models that allow multiple peaks have an inferior fit to the data.

Figure 4. Illustrative examples.

This figure gives illustrative examples of NGF populations predicted by our model. At ages 20 weeks, birth, 13 years, 25 years and 35 years the average NGF population is given, together with the respective 95% prediction intervals. The predicted average age at menopause (49.6 years) is also shown, together with the 95% prediction interval.

Figure 5. Percentage of ovarian reserve related to increasing age.

The curve describes the percentage of ovarian reserve remaining at ages from birth to 55 years, based on the ADC model. 100% is taken to be the maximum ovarian reserve, occurring at 18–22 weeks post-conception. The percentages apply to all women whose ovarian reserve declines in line with our model (i.e. late and early menopause are associated with high and low peak NGF populations, respectively). We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains.

Figure 6. A hypothetical link between ovarian reserve and age at menopause.

This figure describes the hypothesis that individual age at menopause is determined by the peak NGF population established at around 20 weeks post-conception. The central curve is the ADC model described in Figures 1 and 4. Above and below are the hypothetical curves for an ovary having log-adjusted peak population varying from the average case by one half, one, one and a half, and two standard deviations. Under this hypothesis, a variation by, for example, one standard deviation in the initial peak population results in a one standard deviation from the average age at menopause.

Figure 7. Rates of NGF recruitment towards maturation.

Each sub-figure describes the absolute number of NGFs recruited per month, for ages from birth to 55 years, based on population decline predicted by the ADC model. Figure 7 (a) - red curve - denotes recruitment for individuals whose decline is in line with the average age at menopause; maximum recruitment of 880 follicles per month occurs at 14 years 2 months. Figure 7 (b) - green curve - denotes recruitment for individuals whose decline is in line with early age at menopause (the lower 95% prediction limit of the model); maximum recruitment of 104 follicles per month occurs at 14 years 2 months. Figure 7 (c) - yellow curve - denote recruitment in line with late age at menopause (the upper 95% prediction limit of the model); maximum recruitment of 7,520 follicles per month occurs at 14 years 2 months.