Fertility, aging and the brain neuroendocrinological studies in female rats

It is well known that fertility decreases in female mammals with advancing age. In women this decrease already starts around the age of 30 and shows a large variation between individuals. The aim of this thesis was to elucidate changes in the reproductive system, especially in the brain, that may underlie the early decline in fertility with age. To this end,neuroendocrinologicalstudies were performed in young and middle-aged females of two rat strains known to differ in the onset of infertility: theWistar(WU) and (UxRP)F1strain.The results of the present thesis confirm the idea that the attenuation of theluteinizinghormone (LH) surge is one of the first indications of reproductive aging in rats. The LH surge is responsible for ovulation. It is induced by feedback mechanisms of ovarian steroid hormonesestradioland progesterone on the brain (i.e. on the secretion ofgonadotropin-releasing hormone) and pituitary gland (i.e. on the secretion of LH and follicle-stimulating hormone (FSH)) that become operative when the ovarian follicles are matured, and involves estrogen and progesterone receptors in the brain.Our results indicate that the attenuation of the LH surge in middle-aged rats likely results from an altered response of the brain toestradioland possibly also progesterone feedback, since we found a dramatic decrease in the number ofestradioland progesterone-containing neurons in several brain areas known to be crucially involved inneuroendocrineregulation of the reproductive axis. In contrast,estradioland progesterone levels were increased ((UxRP)F1) or even unchanged (Wistar) and the pituitary LH response toGnRHas well as the follicular progesterone production during the LH surge appeared to be comparable between young and middle-aged rats. This suggests that pituitary and ovary functions were still intact. Therefore, changes at the level of the brain may be at the start of the decline in fertility with age in rats.Interestingly, we found strain differences in the regulation of the reproductive axis. There was, for instance, a difference between F1 andWistarrats in the magnitude of the LH surge (F1>Wistar) and the magnitude of the pituitary LH response toGnRH(F1<Wistar). Also, middle-aged F1 rats appeared to be reproductively aged to a further extend compared toWistarrats, as judged by the number of changes in the reproductive system.Although in women ovarian aging appears to be the dominant reason for fertility decline, there is evidence for considerable variation between individuals in the mechanisms underlying reproductive aging. Based on our present findings and literature, we hypothesize that hypothalamic aging may also contribute to the decline in fertility in some women.