Estrogen Receptor Null Mice - Endocrine Reviews
Estrogen Receptor Null Mice - Endocrine Reviews
Estrogen Receptor Null Mice - Endocrine Reviews
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June, 1999 ESTROGEN RECEPTOR NULL MICE 393<br />
FIG. 8.In situ hybridization for progesterone receptor (PR) mRNA in female WT and �ERKO hypothalamus. A, PR mRNA was detected in the<br />
medial preoptic nucleus of wild-type (a) and �ERKO females (b) 5 days afer ovariectomy. Also shown is the increased detection of PR mRNA<br />
in ovariectomized wild-type (c) and �ERKO (d) females 6 h after treatment with 5 �g of estradiol. Asterisks indicate the third ventricle. B,<br />
Quantitative analysis of the hybridization signal shown in panel A. Note the dramatic increase in PR hybridization signal when ovariectomized<br />
(OVX) wild-type mice were treated with estradiol (E 2). Similarly, the hybridization signal seen in intact �ERKO females is attenuated by<br />
ovariectomy, but augmented to intact levels when ovariectomized females were treated with estradiol. Statistical significance is indicated as<br />
follows: **, P � 0.01, ***, P � 0.001. [Reproduced with permission from P. J. Shughrue et al.: Proc Natl Acad Sci USA 94:11008–11012, 1997<br />
(400). © National Academy of Sciences, USA]<br />
rons. Unlike most sexually dimorphic nuclei, the AVPV is<br />
actually larger and composed of a greater number of dopaminergic<br />
neurons in the female compared with the male<br />
(402). In male rodents, this region is rendered inoperative by<br />
the actions of testosterone during differentiation (365), an<br />
effect that can be reproduced in females with neonatal testosterone<br />
or estradiol exposure (403, 404). Therefore, masculinization<br />
of this portion of the brain involves the destruction<br />
of a large portion of these neurons and is believed to be<br />
due to local aromatization of testosterone to estradiol and<br />
subsequent activation of ER-mediated pathways (405). In<br />
support of this hypothesis, Simerly et al. (405) reported that<br />
the AVPV region of �ERKO males possess a population of<br />
dopaminergic neurons more characteristic of a wild-type<br />
female, confirming a critical role of ER� in this differentiation<br />
process. Furthermore, the numbers of dopaminergic neurons<br />
in the female �ERKO are only slightly reduced when compared<br />
with wild-type, indicating a morphologically normal<br />
AVPV region (405). Therefore, with the �ERKO female exhibiting<br />
an apparent preservation of estrogen-induced increases<br />
in hypothalamic PR and a wild-type-like female phenotype<br />
in the AVPV region, it is conceivable that the<br />
hypothalamic mechanisms required for induction of the preovulatory<br />
surge may be intact.<br />
3. Males: gonadotropin regulation. Because of the more prominent<br />
role of testosterone in the male, certain issues specific<br />
to the male hypothalamic-pituitary axis are worthy of discussion.<br />
Of course, lower aromatase activity in the testis<br />
results in circulating levels of estradiol in the male that do not<br />
approach those observed in the intact cycling female. Therefore,<br />
it would be expected that distinct mechanisms of steroid<br />
feedback and regulation of gonadotropin synthesis and secretion<br />
from the hypothalamic-pituitary axis have evolved in<br />
males, presumably one likely to be more dependent on tes-<br />
tosterone. This difference is thought to occur at the level of<br />
the hypothalamus since the anterior pituitary generally exhibits<br />
no sexual differentiation (365) and possesses receptors<br />
for all sex steroids (339).<br />
A critical role of testosterone and AR-mediated actions in<br />
the negative regulation of gonadotropin secretion in the male<br />
is illustrated by the elevated serum LH levels in Tfm mice<br />
(301) and in humans with androgen insensitivity syndromes<br />
(38). As in the female, transcription of the gonadotropin<br />
subunit genes is significantly elevated after castration in the<br />
male, although peak levels are reached much earlier (�7<br />
days) (373). Furthermore, FSH� mRNA levels appear to return<br />
to precastration levels by 28 days, whereas the levels of<br />
LH� and �GSU transcripts remain elevated (373). Estradiol<br />
is equally effective as testosterone in reducing serum LH<br />
levels that result after castration in the male (reviewed in Ref.<br />
373). These data, along with the documented presence of<br />
P450 arom activity (reviewed in Refs. 406 and 407) and wide<br />
distribution of ER in the hypothalamic-pituitary axis support<br />
a role for locally synthesized estradiol and ER action in male<br />
gonadotropin synthesis and/or secretion (88, 339). Furthermore,<br />
adult male ArKO mice exhibit elevated levels of serum<br />
LH despite possessing significantly high circulating testosterone<br />
(257). Therefore, the roles of estradiol and testosterone<br />
often appear overlapping as well as distinct, making obvious<br />
the complexity of the steroid-feedback mechanisms that exist<br />
in the male.<br />
Any specific role the ER� may play in the regulation of<br />
gonadotropin synthesis and secretion in the male would be<br />
expected to become apparent in the �ERKO. Adult �ERKO<br />
males exhibit levels of hypothalamic GnRH, pituitary FSH�<br />
mRNA, and serum FSH that are within the normal range<br />
when compared with wild-type littermates (Table 2) (317).<br />
The normal levels of FSH� mRNA in the pituitary of �ERKO