Reproductive ageing and the menopause.

This brief review describes early work initiated by Anne McLaren and John Biggers, in which they repeated on mice a very early experiment carried out by John Hunter on pigs, to test the effect of unilateral ovariectomy on subsequent breeding performance. This and subsequent experiments led to the conclusion that reproductive ageing in the female mouse was largely due to ageing changes in the uterus. As a result of these changes fewer implanted blastocysts are carried to term in the older females, with the result that the size of litters produced gradually drops and ceases altogether well before the expected time of death, thus leading to a period of reproductive inactivity at the end of life. Other organs undergo ageing changes but it appears to be those in the uterus which limit reproductive performance in the female. The somatic organs concerned in bringing the male gametes into the environment are still able to function effectively almost until the time of death so that males have a very short period of reproductive inactivity at the end of their lives. Due to the prenatal onset of meiosis in the germ cells, female mammals and some, but not all, other vertebrates are born with a finite crop of oocytes in the ovary, which cannot be increased after birth. Nevertheless, with the exception of women, female mammals appear to be able to produce ova well into old age, and have them fertilized. When examined after death the ovaries still contain oocytes so this is not a limiting factor in reproduction in old females. In women the situation is completely different. They also have an extended period of reproductive quiescence in middle and old age, the menopause, but, unlike other female mammals, this is not due to failure of the uterus but is caused by the ovary becoming depleted of oocytes in middle age. The reason women run out of oocytes before the end of life, whereas the other mammals which have been studied do not, is associated with the greatly extended lifespan of humans compared to other mammals of equivalent size. There is a linear relationship between longevity and body weight in mammals, small mammals have much shorter lives than large ones. This is probably associated with the increased production of free radical oxygen necessary to maintain body temperature in smaller animals. Heat is lost through the body surface which becomes relatively less as the animal increases in weight, so the smaller animal has to metabolise and thus produces more free radical oxygen to maintain body temperature. For reasons unknown this seems not to apply to humans. The menopause has thus evolved as a consequence of two adaptations: the prenatal onset of meiosis, common to all mammals and many other vertebrates and the greatly increased longevity of all humans, both male and female. In view of this dual origin it is unlikely to have evolved in response to an adaptive need to have grandmothers to help rear the young, as has been suggested!