Follicle dynamics during ovarian ageing

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Abstract

The human ovary is endowed at birth with a fixed number of primordial follicles which steadily declines throughout life as a result of atresia and recruitment towards ovulation. The pattern of this decline is not exponential, but more bi-exponential corresponding to a ‘broken-stick’ regression of logged total numbers of follicles against age. Such a model implies an abrupt change in the exponential rate of follicle loss at age 38 years, and is thus rather implausible biologically. A more refined model with an exponential rate of follicle loss that changes gradually throughout life also describes the data on declining follicle numbers but in addition leads to a distribution of age at menopause, corresponding to follicle numbers falling below a critical threshold, that shows quite remarkable agreement with independent data on menopausal ages of American women. When the follicles are classified into resting and growing stages, it is found that any changes in the consequent process of follicle development as the ovary ages relate mainly to the small resting follicles and not the larger growing ones.

Introduction

The human female is born with a fixed stock of ovarian follicles which must serve her reproductive needs throughout life. The number of these follicles declines with age as a result of atresia and recruitment towards ovulation; indeed, this decline begins before birth, as the peak number of follicles is reached some months before the end of gestation (Baker, 1963). The pattern of this decline with age is of interest, as it appears to be quite different from that seen in laboratory rodents (Faddy et al., 1983, Faddy et al., 1992). The decline observed from data on human follicle numbers does lead to premature exhaustion of the follicle store and menopause before the end of life (Richardson et al., 1987).

This paper is concerned with modelling the dynamics of the process of follicle decline. Data on estimated numbers of follicles in the ovaries of females of different ages are available (Block, 1952, Block, 1953, Richardson et al., 1987, Gougeon et al., 1994). Mathematical models of the process of follicle decline of varying degrees of complexity can be constructed from these data using least squares estimation: from simple regression based models to more detailed compartmental models. Changes in the components of growth and atresia of the follicles are apparent as the ovary ages and these changes can be linked to the occurrence of menopause in middle-aged women.

Section snippets

Models for follicle decline

A basic model for data that show temporal decline is exponential decay:y=Aexp−bxor linear decay after a logarithmic transformation:logy=logA−bxHere x refers to age and y to the number of follicles, and the parameter b(>0) is the rate of the exponential decay. Simple regression-based analyses of logged numbers of follicles against age can be done to estimate b; for example, total numbers of rodent follicles (Faddy et al., 1983) show approximate exponential decay with age.

However, human ovarian

Compartmental modelling of follicle growth and atresia

Faddy and Gosden (1995) considered a subset of the data on total follicle numbers, where the follicles had been classified into different stages of growth with Stage I being primordial or ‘resting’ follicles described as small unilaminar follicles with a single layer of squamous pre-granulosa cells. With follicles classified into either this Stage I or Stage II consisting of all larger growing follicles, a compartmental model for the consequent process of follicle development can be

Concluding remarks

From the modelling described in this paper, ovarian follicle dynamics can be characterised by some quite dramatic changes as the ovary ages. Low rates of atresia and high rates of growth of small primordial follicles are apparent in the young ovary. But as the ovary ages this state of affairs reverses with high rates of atresia and low rates of growth describing the old ovary. Such a perverse reduction in the functionality of the ovary as it ages contributes to ovarian failure relatively early

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