Estrogen Receptor Null Mice - Endocrine Reviews

June, 1999 ESTROGEN RECEPTOR NULL MICE 397
The elevated levels of infanticide and aggressive behavior
exhibited by the �ERKO females may be contributed to by
the elevated levels of testosterone secreted by the acyclic
ovary (Table 2). As discussed earlier, experimental evidence
suggests that disruption of the ER� gene has resulted in a
hypothalamic-pituitary axis with an enhanced capacity to
respond to androgens in the �ERKO male. In support of this
possibility, Ogawa et al. (418, 426) reported their preliminary
finding of increased androgen receptor levels in the brain of
the �ERKO female as early as 12 days of age.
2. �ERKO male. Given the apparent role of ER�-mediated
estrogen actions in the masculinization of the brain, it was
expected that the �ERKO males would exhibit a female-like
behavioral phenotype. Surprisingly, however, Ogawa et al.
(318) observed that a lack of hypothalamic ER� during development
has little effect on the sexual behavior of the intact
�ERKO male in terms of mounting and sexual attraction
toward wild-type females. In contrast, Wersinger et al. (427)
report that tests of male sexual behavior carried out in a
neutral arena, as opposed to the male’s home cage as done
in the study of Ogawa et al., demonstrates that the number
of mounting attempts exhibited by the �ERKO males is reduced.
Interestingly, the studies of Ogawa et al. illustrated
that �ERKO males, however, exhibit an almost complete lack
of intromission and ejaculation, even though the number and
frequency of mounts were similar to those of wild-type males
(318). Furthermore, treatment of castrated males with estradiol
or the nonaromatizable androgen, DHT, resulted in no
differences in sexual behavior compared with the findings in
the intact �ERKO males (428). These results differ from those
described by Ono et al. (429) and Olsen (131) in the androgeninsensitive
Tfm mouse, which exhibits no male-like sexual
behavior including a lack of mounting as well as intromission
and ejaculation. However, the �ERKO and Tfm males are
similar in terms of exhibiting complete insensitivity to the
effects of both estradiol and testosterone as behavioral activators
during adulthood.
The �ERKO male behavioral phenotype described above
is obviously a contributing factor to the infertility that results
after disruption of the ER� gene. The culmination of the
studies indicate that a discrete component of sexual behavior
in the male mouse, i.e., consummatory activity, is dependent
on the actions of ER�, whereas testosterone or possibly ER�mediated
estradiol actions may regulate motivational aspects
(428). Although reports of categorical studies on sexual
behavior are not available, both the �ERKO (47) and ArKO
(257) male mice appear to be fertile and able to sire multiple
litters, suggesting a minor role for ER� in sexual behavior.
The possibility of compensatory mechanisms mediated by
ER� in the �ERKO cannot be ruled out. It is interesting,
however, that the ArKO males, presumably lacking physiological
levels of estradiol throughout life, show no obvious
deficits in sexual behavior that result in infertility (257). It
might be expected, given the apparent need of ER�-mediated
estrogen actions illustrated by the �ERKO, that the ArKO
male would display a similar phenotype. Perhaps, exposure
to maternal steroid hormones during gestation in the ArKO
mouse has allowed for the proper “organization” of the
neuronal circuitry regulating sexual behavior. More detailed
studies may elucidate subtle behavioral phenotypes that exist
in both the �ERKO and ArKO models and will help
further define the precise role that estradiol and testosterone
play in the regulation of sexual behavior.
A dichotomy similar to that observed for the elements of
male sexual behavior in the �ERKO is observed when behavioral
assays for aggression and parental instincts are considered.
Intact �ERKO males demonstrate a relatively normal
pattern of parental behavior as measured by levels of
infanticide when placed in the presence of newborn pups
(428). However, despite the fact that �ERKO males possess
serum testosterone levels that exceed the norm by as much
as 2-fold and show no reduction in the levels of AR (430) or
ER� (93, 352) in the brain, they consistently exhibit a significant
deficit in all male aggression indices tested (428, 430).
Therefore, as in the case of certain components of sexual
behavior, ER�-mediated actions appear critical to the development
and/or activation of aggressive behaviors, whereas
parental instincts appear to be independent of ER� action
(428).
VII. Phenotypes in Peripheral Tissues
The ER and the estrogen-signaling pathway have been
described in several peripheral organ systems (reviewed in
Ref. 431). A discussion of the phenotypes that may occur in
each of these after disruption of either of the ER genes is
beyond the scope of this review. Therefore, we have chosen
to focus on three areas, all of which have received great
attention as sites of estrogen action that are critical to human
health. These are the bone, cardiovascular system, and adipogenesis.
Furthermore, studies toward specifically defining
a role that ER may play in mediating the actions of
estrogen in each of these systems have begun to employ the
�ERKO, and eventually the �ERKO.
A. Skeletal system
The link between the onset of osteoporosis and the decreasing
estrogen levels associated with menopause has been
realized since the report of Albright et al. in 1941 (432). Postmenopausal
estrogen replacement therapy is currently the
most commonly prescribed drug treatment in the United
States (433, 434). In most patients, the increased risks associated
with long-term estrogen replacement therapy, such as
breast and endometrial cancer, are strongly overshadowed
by the well established reduction in the risk of osteoporosis
and bone fracture (433). Bone is a dynamic tissue that is
constantly being resorbed to serve as a mineral source for the
body and remodeled to replace this reservoir as well as
maintain skeletal strength. Osteoporosis is a defined pathology
characterized by a loss in bone mass and strength and
is believed to be due to a disruption in the equilibrium
between bone resorption and formation (435). Current evidence
supports the hypothesis that excess bone resorption
occurs in the postmenopausal years, acting to strip the bone
of mass and further remove the foundation upon which new
bone may be formed (435). Several therapies are known to
reduce the postmenopausal increases in bone resorption,
including the intake of calcium and vitamin D, calcitonin,