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 403<br />
istics associated with PCOS, also do not demonstrate this<br />
phenotype (254, 255). Several of the endocrine parameters<br />
associated with human PCOS are also observed in the<br />
�ERKO, especially the presence of elevated serum androgens<br />
and LH. Although the observation of hirsutism caused by<br />
elevated serum androgens is not possible in mice, analogous<br />
biological manifestations of elevated androgen levels are<br />
exhibited in the �ERKO female, including masculinized preputial<br />
(clitoral) glands and a thickened dermis. Furthermore,<br />
obesity is reported in a large proportion of PCOS patients and<br />
is thought to be a contributory factor in the extragonadal<br />
conversion of androgens to estrogens. As described above<br />
(Section VII.C), adult �ERKO females significantly outweigh<br />
their age-matched wild-type littermates because of excessive<br />
white adipose tissue. Interestingly, insulin resistance and<br />
hyperinsulinemia are often reported in PCOS patients and<br />
thought to contribute to further androgen synthesis in the<br />
ovarian thecum (204, 487). Taylor and Lubahn (490) reported<br />
an abnormal glucose tolerance test in �ERKO females that<br />
could be corrected with ovariectomy, suggesting PCOS-like<br />
insulin resistance. Therefore, the similarities of the endocrine<br />
abnormalities and ovarian phenotypes in the �ERKO and<br />
bLH�-CTP mice with those of human PCOS patients provide<br />
support that the cause may be extragonadal in nature, and<br />
possibly due to elevated LH in the presence of normal FSH.<br />
Although the initial cause of the abnormally high LH levels<br />
in �ERKO females may differ from that postulated in the<br />
PCOS patient, the resulting effects on the ovary are similar<br />
and may allow the �ERKO to be a useful experimental model<br />
in future investigations of this human disease.<br />
C. ER� and aromatase deficiency<br />
The first and only reported case of estrogen insensitivity<br />
in a human is that of Smith et al. (116) in which a male (46,<br />
XY) was determined to be homozygous for a single-point<br />
mutation in exon 2 of the ER� gene that resulted in a premature<br />
stop codon. Similar reports of human estrogen deficiency<br />
were also lacking in the clinical literature until recently.<br />
However, five cases of aromatase deficiency and<br />
therefore a lack of estrogen synthesis have been reported in<br />
both human males (119, 120) and females (117, 118, 120, 491).<br />
Therefore, the existence of humans that exhibit insufficient<br />
estrogen action due to either a lack of functional receptor or<br />
hormone, along with the successful generation of the ER null<br />
mice, suggests that estrogen is not essential to embryonic and<br />
fetal development in mammals. However, like the ER null<br />
mice, a distinct syndrome of phenotypes is apparent in both<br />
sexes of humans lacking in estradiol or ER.<br />
All three reports of females homozygous for inactivating<br />
mutations in the P450 arom gene describe pseudohermaphroditism,<br />
i.e., 46XX genotype, the presence of internal female<br />
reproductive structures but ambiguous external genitalia<br />
(117, 120, 491). This phenotype is due to the lack of aromatase<br />
activity in the fetus and placental unit during gestation,<br />
leading to the accumulation of androgens, which in turn elicit<br />
masculinizing effects on the fetus (117, 120, 491). A similar<br />
phenotype of ambiguous external genitalia was described in<br />
an infant in which placental aromatase deficiency was determined,<br />
although enzyme activity in the fetus was not<br />
evaluated at the time of the report (118). In the two cases of<br />
a complete lack of aromatase, the mother also exhibited virilization<br />
during pregnancy (120, 491), whereas a traceable<br />
level of placental aromatase activity appeared to inhibit this<br />
symptom in the case of Conte et al. (117). In all three cases,<br />
development of the internal structures of the female reproductive<br />
tract did not appear to be altered by a lack of estrogen<br />
action (117, 120, 491), although a compensatory role fulfilled<br />
by maternal estrogens cannot be ruled out. Serum levels of<br />
androgen, androgen precursors, FSH, and LH were elevated<br />
in the P450 arom-deficient patients as early as infancy (117,<br />
491) and continued to be elevated as the females approached<br />
puberty (117, 120). At 12–14 yr of age, secondary development<br />
of the breasts, a pubertal growth spurt, and menarche<br />
were all absent, but virilization of the external genitalia was<br />
reported (117, 120). In all three cases, hyperstimulation of the<br />
ovary and the development of multifollicular cysts was illustrated,<br />
even as early as 2 yr of age (117, 120, 491). The<br />
ovarian pathology exhibited was similar to that observed in<br />
the �ERKO females and was compatible with a diagnosis of<br />
PCOS (120). Therefore, intraovarian estrogen action does not<br />
appear to play a role in the development of the multifollicular<br />
ovarian cysts in humans. <strong>Estrogen</strong> and progesterone replacement<br />
therapy alleviated the above phenotypes, resulting in<br />
normal gonadotropin and androgen levels, regression of the<br />
ovarian cysts, and in the two pubertal patients reported, the<br />
onset of breast development, a growth spurt, and menarche<br />
(117, 120, 491).<br />
The clinical syndromes exhibited by the two reported human<br />
male cases of aromatase deficiency (119, 120) and the<br />
single known human case of an inactivating mutation of the<br />
ER� gene (116) are strikingly similar. All three patients exhibited<br />
a normal onset of puberty and no gender-identity<br />
disorders, as well as normal external genitalia and prostate<br />
size (116, 119, 120). The patient lacking functional ER� exhibited<br />
a testicular volume and sperm density within the<br />
norm for men of his age (116). A normal testicular volume<br />
was also reported in the P450 arom-deficient patient of Morishima<br />
et al. (120). However, Carani et al. (119) reported small<br />
testis and severe oligozoospermia and infertility in the other<br />
male lacking aromatase, although the presence of similar<br />
findings in a brother with a normal P450 arom gene suggested<br />
other possible familial factors for this finding. Serum levels<br />
of androgens, FSH, and LH were all consistently elevated in<br />
the P450 arom-deficient males (119, 120), as well as estrone and<br />
estradiol in the ER�-deficient male (116). <strong>Estrogen</strong> replacement<br />
therapy resulted in the return of androgen and gonadotropin<br />
levels to the normal range in the P450 arom-deficient<br />
males. However, similar estrogen therapy induced no such<br />
changes in the ER�-deficient male (116). In fact, estrogen<br />
replacement therapy in the ER�-deficient male achieved circulating<br />
levels of the steroid that exceeded the norm by<br />
nearly 5-fold, yet no alleviation of the above pathologies or<br />
side effects were observed, such as impotence and gynecomastia<br />
(116). Alterations in the cardiovascular system have<br />
been reported recently in the ER�-deficient male, including<br />
dysfunctions in vasodilation (492) and premature coronary<br />
artery disease (493).<br />
The most overt phenotypes in all patients lacking sufficient<br />
estrogen action involved the skeleton. Females homozygous