Reproduction and ageing are processes in which bioiogical order and
organization vary over time. Arguably, neither is a biological discipline in
its own right but both involve many branches of science: from molecular
aspects, through studies of the whole organism to an appreciation of the
behaviour of communities. In both fields, therefore, an interdisciplinary
attitude is advantageous and has influenced the course of my research
programme. Investigations of the ageing reproductive system and the
developmental biology of ovarian follicles have involved cytology and
cytogenetics, endocrinology, experimental surgery and mathematical modelling.
Maternal age is a major factor affecting the prospect and outcome of
pregnancy in animals and man. Inbred mice have been used as subjects of most
studies for practical reasons and because they are good models for mammalian
development and ageing. Pregnancy losses in mid-life are attributable to
increased numbers of cytogenetically abnormal embryos and a decreased uterine
capacity for maintaining conceptuses to full term. The cause(s) of aneuploidy
in older mothers remains unknown although the integrity of the meiotic
spindle is in question since it disintegrates during "overripening" of
oocytes in the fallopian tube and is altered in preovulatory oocytes of older
mothers. Experimental delay of ovulation does not affect the incidence of
anomalies but unilateral ovariectomy causes the peak incidence of anomalies
and subsequent sterility to occur prematurely, indicating that biological and
chronological age can be uncoupled. However, many normal conceptuses fail to
thrive in older mothers. The uterus undergoes structural changes as a result
of ageing and parity, but the functional significance of these, if any, is
not known. The endocrinology of pregnancy requires further study for, while
luteal function may be unimpaired, there is mounting evidence of age changes in tissue responsiveness and of detrimental effects of long-term exposure to
cycles of ovarian hormone stimulation.
Ovarian oocytes disappear continuously throughout life because of
recruitment for growth and ovulation, and cell death. Whereas sterility in
some rodents is due to inability to produce an ovulatory surge of
gonadotrophic hormones, in others it is depletion of oocytes, as in humans,
that is primary. The rate of oocyte depletion and the size of the initial
store define the ultimate limit for fecundity. Exponential functions which
define the rates of follicle attrition change according to age and
physiological state. The numbers of follicles at puberty are related
allometrically to body weight, and the early age of menopause in our species
may have arisen adventitiously as longevity evolved beyond expectations based
on body weight.
New techniques have been employed to investigate the control of ovarian
follicle recruitment, growth /death and morphogenesis of the antrum.
Mathematical models indicate that the profile of follicle stages in mice of
different ages and genotypes is mainly influenced by death ("atresia") rates
which are highest in small and large follicles. The granulosa epithelium,
which originates from a small number of clones, controls the formation of the
antrum. Antral fluid appears to consist of local metabolites and plasma
constituents; its formation probably involves more than one mechanism.
Organotypic cultures may provide the best prospect of furthering
investigation of morphogenesis of the Graafian follicle and of the cellular
basis of follicle dynamics.