Submitted October 3, 2006
Returned for revision October 23, 2006
Accepted March 6, 2007
Pituitary
Anterior Pituitary Gene Expression with Reproductive Aging
in the Female Rat
Weiming Zheng ,
Mercedes Jimenez-Linan ,
Beverly S. Rubin ,
and
Lisa M. Halvorson *
* To whom correspondence should be addressed. E-mail: lisa.halvorson{at}utsouthwestern.edu.
Abstract
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 gonadotrope function including a) steroid
hormone receptors (Esr and Pgr), b) orphan
nuclear receptors [Nr5a1 (steroidogenic factor-1)
and Nr5a2 (liver receptor homologue-1)], and c)
pituitary-derived polypeptides (activin, inhibin and
follistatin) as well as d) gonadotropin subunits and e)
GnRH receptors. We chose to utilize a middle-age rat model
for these studies. Young (Y; 3 month old) and middle-aged
(MA; 9-12 month 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 post-ovariectomy and during the
steroid-induced surge in middle-aged rats. We propose that
age-related changes in pituitary physiology may contribute
to reproductive senescence.
Key words:
Pituitary •
Aging •
Follistatin •
Gene regulation •
Steroid hormone receptors
