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Knockout Mice
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology (J.L., J.F.C., K.S.K.) and Hormone Action Group (W.C.W.), Laboratory of Signal Transduction, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; the Department of Psychiatry and Behavioral Sciences, Duke University (W.C.W.), Durham, North Carolina 27710; the Reproductive Toxicology Division, Environmental Protection Agency (T.S., R.C.), Research Triangle Park, North Carolina 27711
Address all correspondence and requests for reprints to: Dr. Kenneth S. Korach, Laboratory of Reproductive and Developmental Toxicology, National Institute for Environmental Health Science, P.O. Box 12233, Research Triangle Park, North Carolina 27709. E-mail: korach{at}niehs.nih.gov
Testicular androgens are integral components of the hormonal feedback
loops that regulate circulating levels of LH and FSH. The sites of
feedback include hypothalamic areas regulating GnRH neurons and
pituitary gonadotropes. To better define the roles of androgen receptor
(AR), estrogen receptor-
(ER), and estrogen receptor-ß (ERß)
in mediating feedback effects of sex steroids on reproductive
neuroendocrine function, we have determined the effects of castration
and steroid replacement therapy on hypothalamic GnRH content, pituitary
LHß and FSHß messenger RNA (mRNA) levels, and serum gonadotropins
in male wild-type (WT) and estrogen receptor- knockout (ERKO) mice.
Hypothalami from intact WT and ERKO males contained similar amounts of
GnRH, whereas castration significantly reduced GnRH contents in both
genotypes. Replacement therapy with estradiol (E2),
testosterone (T), or dihydrotestosterone (DHT) restored hypothalamic
GnRH content in castrated (CAST) WT mice; only the androgens were
effective in CAST ERKOs.
Analyses of pituitary function revealed that LHß mRNA and serum LH levels in intact ERKOs were 2-fold higher than those in intact WT males. Castration increased levels of LHß mRNA (1.5- to 2-fold) and serum LH (4- to 5-fold) in both genotypes. Both E2 and T treatments significantly suppressed LHß mRNA and serum LH levels in CAST WT males. However, E2 was completely ineffective, and T was only partially effective in suppressing these two indexes in the CAST ERKO males. DHT treatments stimulated a 50% increase in LHß mRNA and serum LH levels in WT males, whereas serum LH was significantly suppressed in DHT-treated ERKO males.
Although the pituitaries from intact ERKO males contained similar amounts of FSHß mRNA, serum FSH levels were 20% higher than those in the intact WT males. Castration increased FSHß mRNA levels only in WT males, but significantly increased serum FSH levels in both genotypes. Both E2 and T treatments significantly suppressed serum FSH in CAST WT males, whereas only E2 suppressed FSHß mRNA. DHT treatments of CAST WT mice stimulated a small increase in serum FSH, but failed to alter FSHß mRNA levels. None of the steroid treatments exerted any significant effect on FSHß mRNA or serum FSH levels in CAST ERKOs.
These data suggest that hypothalamic GnRH contents can be maintained
solely through AR signaling pathways. However, normal regulation of
gonadotrope function requires aromatization of T and activation of
ER signaling pathways in the gonadotrope. In addition, serum FSH
levels in male ERKOs appear to be regulated largely by nonsteroidal
testicular factors such as inhibin. Finally, these data suggest that
hypothalamic ERß may not be involved in mediating the negative
feedback effects of T on serum LH and FSH in male mice.
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