Alterations in the Postovariectomy Increases in Gonadotropin Secretion in Middle-Aged Persistent-Estrous Rats: Correlation with Pituitary Gonadotropin Subunit Gene Expression

Abstract

This study compared the changes in pituitary and serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) at various times following ovariectomy (OVX) between young cyclic and middle-aged persistent-estrous (PE) rats and related these to the relative gene expression of the pituitary gonadotropin subunits. In intact animals, both pituitary and serum levels of LH were similar between these two age groups, while the LHβ mRNA expression was significantly (p < 0.05) greater in young rats. Following OVX in young rats, the serum LH levels markedly increased (p < 0.05) beginning on day 7 and reaching a maximum fourfold increase by day 9. In contrast, the post-OVX increases in serum LH in middle-aged females were significantly delayed. OVX significantly (p < 0.05) increased pituitary LH contents of young rats by day 5, but had no effect on LH contents in middle-aged females until day 30 post-OVX. These changes were associated with increases in LHβ mRNA expression in both young and middle-aged females, but the levels were significantly (p < 0.05) lower in middle-aged females. Both pituitary and serum levels of FSH were significantly (p < 0.05) higher in middle-aged PE than in young rats prior to OVX, while the FSHβ mRNA expression was similar in both age groups. Following OVX in young rats, serum FSH levels rapidly increased (p < 0.05) on day 3 and attained tenfold higher values by day 30. In middle-aged PE females, OVX also produced a similar pattern of changes in serum FSH as in young rats, but the levels were significantly (p < 0.05) lower than those of young rats. Following OVX, both young and middle-aged rats showed similar and marked (five- to tenfold) increases in pituitary FSH contents. After OVX, young rats exhibited an immediate and marked (seven- to tenfold) increase in FSHβ mRNA expression, while middle-aged females showed a similar but a smaller (p < 0.05) magnitude (sixfold) of increase. Alpha mRNA expression showed modest and variable increases in young rats following OVX, while alpha mRNA expression in PE females did not significantly change and was lower (p < 0.01) than that in young rats. These results demonstrate that the post-OVX increases in pituitary gonadotropin secretion were associated with similar changes in the gene expression of the subunits and that delayed and/or attenuated increases in LH and FSH secretion seen in OVX, middle-aged PE females were related to smaller increases in α- and β-subunit mRNA expression. Inasmuch as hypothalamic secretion of gonadotropin-releasing hormone (GnRH) is important in regulating LHβ and FSHβ mRNA expression, the present findings suggest that altered gonadotropin secretion in aging rats may be related to decreased GnRH release and/or an impaired pituitary mechanism to GnRH stimulation.

Anterior Pituitary Gene Expression with Reproductive Aging in the Female Rat1

“…The combined results of our in vivo and in vitro data are consistent with a loss of Nr5a1 basal expression and steroid responsiveness but not GnRH responsiveness in aging gonadotrophs. This age-dependent decrease in Nr5a1 expression may provide a molecular mechanism by which gonadotropin biosynthesis decreases with age, leading to an attenuated LH peak in MA rats as reported previously [6,10,64].…”

“…GnRH expression is known to be blunted in aging animals and this change may explain, in part, the decrease in follistatin gene expression. While gonadotropin gene expression is decreased in the early stages of middle-age reproductive dysfunction, it is also known that perimenopausal women and middle-aged persistent-estrus rats ultimately experience an increase in plasma FSH levels [6,[73][74][75][76][77]. Therefore, the observed loss of follistatin expression and regulation may foreshadow the eventual increase in gonadotropin expression.…”

“…Prior to obvious changes in the reproductive cycle, middle-aged (MA) rats (generally defined as 8-14 mo of age) demonstrate delayed and attenuated luteinizing hormone (LH) surges relative to young (Y) females on proestrus and following ovariectomy and steroid priming [4,5]. Aging females also demonstrate a blunted and delayed postovariectomy rise in gonadotropin levels [6]. This abnormal response persists in animals downregulated with continuous GnRH prior to ovariectomy, suggesting primary neuroendocrine dysfunction [7].…”

“…Lhb mRNA levels are decreased at noon on proestrus in middle-aged rats with an attenuated preovulatory surge [10]. Similarly, persistent estrus rats express decreased Lhb mRNA levels and demonstrate a blunted increase in all three gonadotropin subunits following ovariectomy [6]. Of note, it is currently not known whether these changes in gonadotroph secretion reflect altered hypothalamic input or are additionally due to primary dysfunction of the pituitary gonadotrophs.…”

Temporal Changes Occur in the Neuroendocrine Control of Gonadotropin Secretion in Aging Female Rats: Role of Progesterone1

“…The changes in the central nervous system of the age-related transition to acyclicity include a decrease in LH pulse frequency, which occurs in parallel with the increase in reproductive decline [34], and a marked delay in the increased LH␤ mRNA expression that usually follows OVX [35]. Reductions in P 4 -receptor (PR) mRNA levels also occur at sites involved in regulation of the LH surge (e.g., the anteroventral periventricular nucleus) of both early and long-term PE rats, supporting the idea of altered PR responsiveness in the hypothalamic-pituitary axis.…”