Estrogen Receptor Null Mice - Endocrine Reviews
Estrogen Receptor Null Mice - Endocrine Reviews
Estrogen Receptor Null Mice - Endocrine Reviews
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392 COUSE AND KORACH Vol. 20, No. 3<br />
pin secretion requires pulsatile stimulation from the<br />
hypothalamus, and each responds differently depending on<br />
the amplitude and frequency of GnRH stimulation (373, 376).<br />
Varied expression of the GnRH receptor on the cell surface<br />
of the gonadotrophs also varies with the level of hypothalamic<br />
stimulation (396). This mechanism, by which the level<br />
GnRH receptors can be differentially regulated and thereby<br />
modify the gonadotropin responsiveness to GnRH, has been<br />
proposed to be a key element in the differential regulation of<br />
the two different gonadotropins by the same releasing hormone<br />
(397). Studies in the rat have revealed that more rapid<br />
GnRH pulses (15–60 min) favor the secretion of LH, whereas<br />
slower pulses (120 min) allow for secretion of FSH (251, 376).<br />
Positive regulation of LH synthesis and secretion is also more<br />
sensitive to the amplitude of GnRH stimulation (251, 376).<br />
Therefore, a loss of ER� action during development and<br />
maturation of the hypothalamic-pituitary axis may have resulted<br />
in a pattern of GnRH secretion that favors the translation<br />
and secretion of LH rather than FSH. The influence that<br />
ER� may have, including a possible compensatory role in the<br />
�ERKO hypothalamus, remains to be evaluated.<br />
2. Female-positive gonadotropin regulation. In addition to maintaining<br />
tonic levels of serum gonadotropins, estradiol also<br />
plays a central role in the preovulatory gonadotropin surge<br />
mode in the female (reviewed in Refs. 263, 264, and 377).<br />
Differentiation of the neuroendocrine system results in the<br />
development of mechanisms necessary to produce a dramatic<br />
preovulatory rise in serum gonadotropins in response<br />
to the positive feedback of ovarian steroids. In the rodent,<br />
developmental differentiation of this pathway in the neuroendocrine<br />
system is unique to the female (365). The surge<br />
in serum LH and FSH is the hallmark of the female cycle and<br />
is critical to ovulation as well as the synchronized induction<br />
of appropriate sexual behavior and, therefore, is vital to the<br />
female ovarian cycle and fertility.<br />
Numerous studies have demonstrated that estradiol is<br />
required for the preovulatory gonadotropin surge, and that<br />
the timing and dose of estradiol exposure may be the most<br />
critical parameters (reviewed in Ref. 377). As with the negative<br />
regulatory effects of estradiol, the precise site of action<br />
for the sex steroids during the preovulatory gonadotropin<br />
surge also remains unclear. However, it is believed to be the<br />
result of the combined effects of external and internal cues<br />
transduced from the brain and the positive feedback of gonadal<br />
hormones that provide for a synchronized pattern of<br />
GnRH secretion upon an anterior pituitary that has been<br />
rendered transiently hypersensitive to the releasing hormone<br />
(reviewed in Ref. 377). In the monkey, destruction of the<br />
neurons involved in GnRH production can be overcome with<br />
pulsatile administration of exogenous GnRH, whereupon a<br />
gonadotropin surge can be produced with exogenous estradiol,<br />
indicating the pituitary as the predominant factor in the<br />
surge (398). However, this is not possible in the rodent,<br />
apparently due to a greater level of interdependency among<br />
the components of the neuroendocrine axis (365).<br />
Therefore, although the rises in ovarian estrogen secretion<br />
are critical to the generation of a gonadotropin surge, the<br />
pathways involved are poorly understood. A number of<br />
mechanisms involving direct actions of estrogen in the brain<br />
have been proposed and recently reviewed (264). However,<br />
it is unlikely that the actions of estrogen are via direct interaction<br />
with GnRH neurons since these processes appear to<br />
be devoid of ER (264). Therefore, the actions of estradiol<br />
appear to result in indirect stimulation of the hypothalamic<br />
neurons that synthesize and release GnRH. Possible mechanisms<br />
include steroid interaction with receptor-positive<br />
monoaminergic and opoid neurons that may mediate the<br />
ultimate effects to GnRH neurons, possibly via modifications<br />
in the levels of catacholamines, glutamate, �-aminobutyric<br />
acid, neuropeptide Y, �-endorphins, and galanin (reviewed<br />
in Refs. 263 and 264). At the level of the anterior pituitary, the<br />
preovulatory increases in estradiol may act in concert with<br />
GnRH to enhance gonadotrope sensitivity to the forthcoming<br />
rise in releasing hormone by increasing the levels of GnRH<br />
receptor (263, 377). Furthermore, the 5�-flanking region of the<br />
rat LH� gene has been shown to possess an imperfect estrogen-responsive<br />
element that is able to bind ER� and confer<br />
estrogen responsiveness to a chimeric promoter-reporter<br />
gene construct in vitro (399). Therefore, the estradiol-ER�<br />
complex may also act to directly increase LH� mRNA levels<br />
before the LH surge (251).<br />
Attempts to elicit an LH surge in the ovariectomized<br />
model with acute estradiol treatments have been reported to<br />
be only partially effective, indicating that ovarian factors<br />
other than estradiol are also required for a full physiological<br />
response (reviewed in Ref. 263). It is now known that the<br />
actions of progesterone and the PR are also a necessary<br />
component in the induction of the gonadotropin surge (reviewed<br />
in Ref. 263). The role of progesterone and PR in<br />
facilitating the preovulatory surge may be to induce a rapid<br />
release of GnRH from the hypothalamus, as well as possibly<br />
mediate a decrease in ER levels in the anterior pituitary,<br />
thereby possibly counteracting the inhibitory effects of estradiol<br />
(263). Although the precise mechanism of action may<br />
be unclear, the complete lack of a preovulatory surge in intact<br />
PRKO female mice provides strong support for the requirement<br />
of this steroid receptor (387).<br />
A cooperative role between the estrogen- and progestronesignaling<br />
pathways in the induction of the preovulatory<br />
surge may include the ability of estradiol to stimulate increased<br />
PR levels in both the hypothalamus and anterior<br />
pituitary, thereby increasing the sensitivity of these tissues to<br />
progesterone (400, 401). Shughrue et al. have shown that<br />
estradiol-induced increases in PR expression in the preoptic<br />
nucleus are possible in the �ERKO female (Fig. 8) and suggest<br />
that this may be a compensatory action of ER� (400).<br />
These same studies demonstrated that the preoptic nucleus<br />
of the hypothalamus in intact �ERKO females possessed a<br />
significantly greater level of PR mRNA when compared with<br />
wild-types, perhaps due to chronic stimulation of ER� by the<br />
elevated serum estradiol (400). Evidence to support this hypothesis<br />
is the apparent decrease in the level of PR transcripts<br />
observed after ovariectomy in the �ERKO, which can be<br />
returned to intact levels 6 h after a single treatment with<br />
estradiol (Fig. 8) (400).<br />
The preoptic area of the hypothalamus, more specifically,<br />
the anteroventral periventricular nucleus of the preoptic region<br />
(AVPV), is thought to play a critical role in transducing<br />
the gonadotropin surge via interactions with the GnRH neu-