Neuroendocrine Mechanisms for Reproductive Senescence in the Female Rat: Gonadotropin-Releasing Hormone Neurons

Abstract

Reproductive aging in female rats is characterized by profound alterations in the neuroendocrine axis. The preovulatory luteinizing hormone (LH) surge is attenuated, and preovulatory expression of the immediate early gene fos in gonadotropin-releasing hormone (GnRH) neurons is substantially reduced in middle-aged compared with young rats. We tested the hypothesis that alterations in GnRH gene expression may be correlated with the attenuation of the LH surge and may be a possible mechanism involved in neuroendocrine senescent changes. Sprague-Dawley rats ages 4 to 5 mo (young), 12-14 mo (middle-aged), or 25 to 26 mo (old) were killed at 10:00 AM or 3:00 PM on proestrus, the day of the LH surge, or diestrus I in cycling rats, and on persistent estrus or persistent diestrus in acyclic rats. RNase protection assays of GnRH mRNA and GnRH primary transcript were performed. GnRH mRNA levels increased significantly with age, whereas GnRH primary transcript levels, an index of GnRH gene transcription, decreased in old compared to young and middle-aged rats. This latter result suggests that an age-related change in GnRH mRNA levels occurs independently of a change in gene transcription, indicating a potential posttranscriptional mechanism. On proestrus, GnRH mRNA levels increased significantly from 10:00 AM to 3:00 PM in young rats. This was in contrast to proestrous middle-aged rats, in which this afternoon increase in GnRH mRNA levels was not observed. Thus, the normal afternoon increase in GnRH mRNA levels on proestrus is disrupted by middle age and may represent a substrate for the attenuation of the preovulatory GnRH/LH surge that occurs in rats of this age, prior to reproductive failure.

Neuroendocrine control of reproductive aging: roles of GnRH neurons

“…Rance's laboratory used in situ hybridization to show that GnRH mRNA levels are significantly higher in postmenopausal than in premenopausal women, the latter of varying menstrual cycle status (Table 1) (Rance & Uswandi 1996). The similarity of Rance's finding in women to our finding in rats (Gore et al 2000a), that is, age-associated increases in GnRH mRNA levels, suggests that, whereas the ovarian environment is very different, the hypothalamic level may be conserved across mammalian species.…”

“…Nevertheless, this diminution of preovulatory GnRH/LH release, which is correlated temporally with diminution in the proestrous increase in GnRH gene expression (Gore et al 2000a), seems to presage the transition to acyclicity. Indeed, both positive and negative feedback regulation of GnRH/LH release become compromised with aging in rats (Huang et al 1976).…”

“…In ovarian-intact Sprague-Dawley female rats, used either on proestrus or diestrus (the two extremes of the estrous cycle), our group used the RNase protection assay to show that overall GnRH mRNA levels are significantly higher in middle-aged (12 -14 months) and old (25 -26 months) than young (4 -5 months) rats (Gore et al 2000a) (Table 1). In these same animals, GnRH primary transcript levels, an index of gene transcription, are significantly lower in old than young or middle-aged rats (Gore et al 2000a). This finding suggests that the ageassociated increase in GnRH mRNA occurs independently of de novo gene transcription; in fact, the increase in mRNA occurs despite a decrease in gene transcription.…”

“…In our study comparing young and middle-aged intact rats during the proestrous gonadotropin surge, we showed that GnRH mRNA levels are higher at 1500 than 1000 h. A trend for the GnRH primary transcript to be increased at 1500 compared with 1000 h was also seen in young rats. By contrast, middle-aged rats lack an increase in GnRH mRNA or primary transcript on proestrus (Gore et al 2000a) (Table 1). This lack of drive of the GnRH system of middle-aged rats may explain the delay and attenuation of the preovulatory GnRH/LH surge.…”

Neuroprotection in Perimenopausal Women

“…The ovaries are stimulated during menopausal transition and early postmenopausal years by gonadotropins, but the pulsatile GnRH pattern is different in different species before reproductive failure. It is a decrease of GnRH gene expression in many middle-aged rats [27], and an increase in perimenopausal rhesus monkeys [28].…”