Attenuated proestrous luteinizing hormone surges in middle-aged rats are associated with decreased pituitary luteinizing hormone-β messenger ribonucleic acid expression

Hogg, Barbara B.; Matt, Dennis W.; Sayles, Timothy E.

doi:10.1016/s0002-9378(11)91405-7

Cited by 8 publications

(5 citation statements)

References 18 publications

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“…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].…”

Section: Discussionsupporting

confidence: 72%

“…Specifically, we expected to confirm previous reports that middle-aged animals experience a delayed and attenuated gonadotropin surge with a correlated decrease in Cga, Lhb, and Fshb mRNA levels as was reported on proestrus [5,10]. We also predicted that Gnrhr levels would be decreased in the older animals relative to young animals based on two reports that middle-aged cycling female rats have a blunted response to GnRH in perifusion [13,36].…”

Section: Introductionsupporting

confidence: 59%

“…In addition to secretory changes, middle-aged animals also demonstrate impaired gonadotropin biosynthesis. 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].…”

Section: Introductionmentioning

confidence: 92%

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Anterior Pituitary Gene Expression with Reproductive Aging in the Female Rat1

Zheng

Jimenez-Liñan

Rubin

et al. 2007

Biology of Reproduction

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Although reproductive aging in women is classically attributed to loss of ovarian follicles, recent data have suggested that the entire hypothalamic-pituitary-ovarian axis undergoes functional changes with time. The aim of this study was to characterize age-related changes in pituitary gene expression for factors with known importance for gonadotroph function, including 1) steroid hormone receptors (Esr and Pgr), 2) orphan nuclear receptors [Nr5a1 (steroidogenic factor-1) and Nr5a2 (liver receptor homologue-1)], and 3) pituitary-derived polypeptides (activin, inhibin, and follistatin), as well as 4) gonadotropin subunits and 5) GnRH receptors. We chose to utilize a middle-aged rat model for these studies. Young (Y; 3-mo-old) and middle-aged (MA; 9- to 12-mo-old) rats were ovariectomized, primed with estradiol, and injected with progesterone to induce an LH surge. The mRNA levels for the gonadotropin subunits and GnRH receptors were decreased in middle-aged females relative to young animals. Nr5a1 and follistatin mRNA levels were significantly greater in Y versus MA animals following ovariectomy. Furthermore, steroid-induced regulation of these genes was lost in the MA animals. Regulation of the Nr5a2, Inhba, and Inhbb transcripts was also limited to the young animals. In contrast, there were no significant differences in the mRNA levels of Esr or Pgr family members between age groups at any time point. Although this in vivo model normalizes ovarian steroid levels, it does not control for potential differences in GnRH stimulation with aging. Therefore, in a second set of experiments, we used an in vitro perifusion system to compare the effects of pulsatile GnRH in the two age groups. Nr5a1 mRNA expression was greater in Y than MA animals and was significantly decreased by GnRH pulses in both age groups. Follistatin mRNA levels increased significantly with GnRH treatment in Y animals but were not significantly changed in the MA females. Taken together, these data demonstrate gene-specific blunting of pituitary gene expression postovariectomy and during the steroid-induced surge in middle-aged rats. We propose that age-related changes in pituitary physiology may contribute to reproductive senescence.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 92%

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Anterior Pituitary Gene Expression with Reproductive Aging in the Female Rat1

Zheng

Jimenez-Liñan

Rubin

et al. 2007

Biology of Reproduction

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“…As previously observed [10], when middle-aged animals with intermediate-to-high peak LH surges were grouped together, their mean LH levels were essentially the same as young animals. These were classified as 'middle-aged normal'.…”

Section: Characterization O F the Proestrous Lh Surgesupporting

confidence: 77%

Luteinizing Hormone Secretion by Dispersed Anterior Pituitary Gland Cells from Middle-Aged Rats

Krieg

Brito²,

Sayles³

et al. 1995

Neuroendocrinology

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Several studies have shown that a certain subpopulation of middle-aged rats have an attenuated preovulatory LH surge, and that this is an early indicator of a general decline in reproductive cyclicity. The pituitary glands of middle-aged animals with attenuated LH surges have been shown to be significantly less responsive to GnRH than those from young (Y) animals. The present study was designed to investigate the relationship between the in vivo LH surge and the in vitro secretory capacity of dispersed anterior pituitary gland cells from the same animals. Individual LH-secreting cells were also studied with respect to their LH secretory capacity and proportionate numbers in the pituitary gland using reverse hemolytic plaque assay (RHPA). Two groups of animals, young (4–5 months old) and middle-aged (10–12 months old), were sampled on the afternoon of proestrus to determine the amplitudes of their preovulatory LH surges. The middle-aged animals were then classified as either normal (MAN) or attenuated (MAA) with regard to the peak levels of the surges. On the next proestrus, dispersed anterior pituitary gland cells were prepared for either perifusion or RHPA. Perifused anterior pituitary gland cells were exposed to three 2.5-min pulses of GnRH (30 nM) at 60-min intervals. In the RHPA, red blood cells were treated with protein-A to allow coating with rabbit antiovine LH-beta, and then co-incubated with anterior pituitary gland cells. The cells were then treated with one of several concentrations of GnRH (0, 0.1, 1.0, 10, or 100 nM). GnRH responsiveness of dispersed anterior pituitary gland cells from MAA animals was decreased compared to cells from Y animals. Comparison of MAA to Y animals showed that proportional LH release was greater in vitro than in vivo. This corroborated results from previous studies using perifused pituitary fragments. Responsiveness of individual LH-secreting cells, as indicated by mean plaque area, was not different between Y and middle-aged rats at 12.00 h. However, the percentage of anterior pituitary gland cells from MAA animals that formed LH plaques were significantly lower than those from Y animals at 12.00 h, under both basal and GnRH-stimulated conditions. These results verify that the pituitary glands of MAA animals are less responsive than those of Y animals, and imply potential changes in GnRH output from the hypothalamus in vivo. They also indicate that the decreased responsiveness of pituitary tissue from MAA animals may be due more to a decrease in the percentage of anterior pituitary gland cells that release LH than to a decrease in LH responsiveness of individual cells.

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“…Moreover, studies in which the aim has been to document whether pituitary LH production and content are altered as a function of age are not entirely consistent. Thus, although some reports suggest that pituitary content and basal release of LH are the same in young and middle-aged rats [31,32], middle-aged rats with attenuated LH surges show a lower expression of LH␤ mRNA during proestrus [31]. Further studies are clearly required to clarify this issue.…”

Section: Discussionmentioning

confidence: 91%

Characterization of Attenuated Proestrous Luteinizing Hormone Surges in Middle-Aged Rats by Deconvolution Analysis1

Matt

Gilson

Sales

et al. 1998

Biology of Reproduction

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Reproductive aging in female rats is associated with attenuated preovulatory LH surges. In this study, detailed analyses of the episodic characteristics of the proestrous LH surge were conducted in young and middle-aged regularly cyclic rats. On proestrus, blood samples were withdrawn at 3-min intervals for 6 h and analyzed for LH concentrations by RIA in triplicate. Deconvolution analysis of immunoreactive LH concentrations revealed that there was no difference in the detectable LH secretory burst frequency between young and middle-aged rats. However, in middle-aged rats with an attenuated LH surge on proestrus, the mass of LH secreted per burst and the maximal rate of LH secretion per burst were only one fourth (p < 0.01) of those in young and middle-aged rats with normal LH surges. Furthermore, middle-aged rats with attenuated LH surges had a 4-fold decrease (p < 0.01) in the maximal rate of LH secretion per burst compared to young and middle-aged females with normal LH surges. The apparent half-life of endogenous LH was similar among the 3 groups. The attenuated LH surges of middle-aged rats were related specifically to a decrease in LH burst amplitude with no change in pulse frequency. The orderliness of moment-to-moment LH release as quantified by the regularity statistic, approximate entropy, was comparable in the 3 groups. Our findings of a markedly decreased amount of LH released per burst and preserved orderliness of the LH release process strongly suggest that a deficient GnRH drive and/or reduced responsivity to the GnRH signal, rather than altered timing of the signal, accounts for the age-related decline in reproductive function in female rats as presaged by an attenuated proestrous LH surge in middle age.

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Attenuated proestrous luteinizing hormone surges in middle-aged rats are associated with decreased pituitary luteinizing hormone-β messenger ribonucleic acid expression

Cited by 8 publications

References 18 publications

Anterior Pituitary Gene Expression with Reproductive Aging in the Female Rat1

Anterior Pituitary Gene Expression with Reproductive Aging in the Female Rat1

Luteinizing Hormone Secretion by Dispersed Anterior Pituitary Gland Cells from Middle-Aged Rats

Characterization of Attenuated Proestrous Luteinizing Hormone Surges in Middle-Aged Rats by Deconvolution Analysis1

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