Estrogen Receptor Null Mice - Endocrine Reviews
Estrogen Receptor Null Mice - Endocrine Reviews
Estrogen Receptor Null Mice - Endocrine Reviews
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394 COUSE AND KORACH Vol. 20, No. 3<br />
males are in stark contrast to the significantly elevated levels<br />
found in the female �ERKO mice (282). This contrast between<br />
the sexes may reflect differences in the inhibin/activin levels<br />
or may represent a definitive sexual differentiation in the<br />
transcriptional regulation of the FSH� gene in the mouse,<br />
indicating that androgens are the primary acting steroids in<br />
the male. However, although not as extreme as those found<br />
in the �ERKO female, pituitary LH� mRNA and serum LH<br />
levels are increased 2-fold in the adult �ERKO male (Table<br />
2) (317).<br />
In a series of experiments, Lindzey et al. (317) demonstrated<br />
that castration results in the expected elevated levels<br />
of serum LH in the wild-type, and a further increase in the<br />
already elevated LH levels in �ERKO males. The rise in<br />
serum LH that occurs upon castration even in the �ERKO<br />
male suggests that either estradiol-ER� or androgen-mediated<br />
mechanisms are maintaining the lower LH levels in the<br />
intact animal. Once again however, the mouse pituitary (including<br />
the �ERKO) appears to possess very little if any ER�<br />
mRNA (93), although ER� is expressed normally in the hypothalamic<br />
regions in the �ERKO (93, 352). Estradiol treatment<br />
of castrated animals over a period of 3 weeks reduced<br />
the serum LH levels to normal in the wild-type males,<br />
whereas no effect was observed in the �ERKO, indicating a<br />
requirement for ER� in this process (317). Although treatments<br />
of similar castrated males with testosterone was completely<br />
effective in producing an inhibitory effect on LH<br />
release in the wild-types, it was only partially effective in the<br />
�ERKO (317). The authors therefore concluded that the ability<br />
of testosterone to fully restore normal levels of LH in the<br />
sera of castrate wild-type males but only partially in the<br />
�ERKO males suggests that local aromatization of testosterone<br />
to estradiol and subsequent activation of ER�-mediated<br />
pathways act to enhance the negative feedback effects of<br />
androgens in the male hypothalamic-pituitary axis (317).<br />
However, the inability of testosterone to completely suppress<br />
the serum LH in the �ERKO male may be related to the<br />
dosage used in these studies. Strong evidence of AR-dependent<br />
regulation of LH secretion in the male �ERKO is found<br />
in preliminary experiments in which treatment with an antiandrogen<br />
(flutamide) increased serum LH by 3- to 10-fold<br />
in wild-type and �ERKO males, respectively. This suggests<br />
that �ERKO males have come to rely entirely on AR-mediated<br />
actions to regulate LH secretion, whereas the ER� continues<br />
to play a role in the wild-type.<br />
In these same studies, Lindzey et al. (317) illustrated that<br />
prolonged treatment with DHT, the more potent and nonaromatizable<br />
androgen, resulted in no reduction in the castrate<br />
levels of serum LH in wild-type but was partially effective<br />
in the �ERKO male. However, the DHT was effective<br />
in restoring hypothalamic GnRH content levels to normal in<br />
castrate males of both genotypes (317). Therefore, the enhanced<br />
effect of DHT in negatively affecting the hypothalamic-pituitary<br />
regulation of serum LH, including the inhibition<br />
of hypothalamic GnRH release, remains a puzzling<br />
phenomenom unique to the �ERKO male. It is possible that<br />
a lack of ER� action during development resulted in a “reorganization”<br />
of the hypothalamic-pituitary axis in the<br />
�ERKO male, and thereby somehow allowed for an increased<br />
sensitivity to androgens (317). Further studies in the<br />
�ERKO as well as the �ERKO males may help elucidate these<br />
unexpected results.<br />
4. PRL regulation. PRL possesses more biological actions than<br />
all of the other anterior pituitary hormones combined. A<br />
recent review by Bole-Feysot et al. (279) thoroughly covered<br />
the current knowledge of the diverse actions of PRL, including<br />
its functions as a hormone, growth factor, neurotransmitter,<br />
and immunoregulator. A reflection of the multiple<br />
functions of PRL is the equally broad distribution of PRLbinding<br />
sites throughout the many physiological systems in<br />
vertebrates (279). The well known effects of PRL in reproduction<br />
include a critical role in the differentiation and function<br />
of the lactating mammary gland, as a luteotrophic hormone<br />
in the function of the corpus luteum and thereby as a<br />
promotor of blastocyst implantation, and an overall enhancement<br />
of the physiological functions in the tissues of the male<br />
reproductive tract (279). Nonreproductive roles of PRL include<br />
an involvement in osmoregulation; promotion of<br />
growth, development, and differentiation in several tissues;<br />
enhancement of metabolic activities in the brain, liver, pancreas,<br />
and adrenals; and various actions in immunoregulation<br />
(279).<br />
It has long been known that estradiol is a critical hormone<br />
in the regulation of PRL synthesis and secretion from the<br />
lactotrophs in the anterior pituitary. Estradiol has also been<br />
shown to stimulate lactotroph cell growth (reviewed in Ref.<br />
281) and has been implicated as a possible factor in the<br />
promotion of PRL-secreting tumors in humans (reviewed in<br />
Ref. 339). Furthermore, the lactotrophs of several species<br />
have been shown to possess significant levels of ER�,<br />
strongly suggesting that the actions of estradiol are receptormediated<br />
(reviewed in Ref. 339). As discussed above, recent<br />
descriptions have indicated the presence of ER� in the lactotrophs<br />
of the rat anterior pituitary, although contrasting<br />
reports exist, possibly due to strain variations. Whereas Wilson<br />
et al. (98) describe the presence of only ER� in lactotrophs,<br />
Mitchner et al. (99) report variable levels of ER�<br />
mRNA throughout the various cell types of the rat anterior<br />
pituitary. Shupnik et al. (100) have also reported the detection<br />
of ER� transcripts in human PRL-secreting tumors. Once<br />
again, we find only low to undetectable levels of ER� mRNA<br />
in the pituitary of the adult mouse, including the �ERKO<br />
(93).<br />
The upstream regulatory sequences of the rat PRL gene<br />
have been found to possess an estrogen-responsive element<br />
that binds ER� and functions synergistically with the pituitary-specific<br />
factor, Pit-1, to promote expression (281, 408,<br />
409). The required function of the ER� in the positive regulation<br />
of the PRL gene is nicely illustrated in the �ERKO<br />
mouse. The �ERKO females exhibit a 20-fold decrease in PRL<br />
mRNA levels in the anterior pituitary, whereas the �ERKO<br />
males exhibit a 10-fold decrease when each is compared with<br />
sex-matched wild-type controls (282). Although not as drastic,<br />
this reduction in the expression of the PRL gene is mirrored<br />
in the serum levels of the hormone in the �ERKO<br />
female, which possess an approximate 5-fold reduction in<br />
serum PRL (Table 2). Therefore, given the plethora of roles<br />
in which PRL is involved, it is likely that several of the<br />
phenotypes observed in the �ERKO mice may be due to a