Characterization of the hypothalamic-pituitary-gonadal axis in estrogen receptor (ER) null mice reveals hypergonadism and endocrine sex reversal in females lacking ERα but not ERβ
Characterization of the hypothalamic-pituitary-gonadal axis in estrogen receptor (ER) null mice reveals hypergonadism and endocrine sex reversal in females lacking ERα but not ERβ
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DOI：
10.1210/me.2002-0398
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发表时间：
2003-06-01
影响因子：
--
通讯作者：
Korach, KS
中科院分区：
文献类型：
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作者：
Couse, JF;Yates, MM;Korach, KS
为了确定每种雌激素受体（ER）形式（ER α，ER β）在介导维持下丘脑-垂体-性腺轴正常功能所需的雌激素作用中的作用，我们对雌性ER敲除（ERKO）小鼠的下丘脑-垂体-性腺轴进行了表征。垂体功能评价包括Gnrhr、Cga、Lhb、Fshb和Prl的基因表达测定。卵巢类固醇生成能力的评价包括雌二醇合成所需组分的基因表达测定：即星星、Cyp 11 a、Cyp 17、Cyp 19、Hsd 3b 1和Hsd 17 b1。通过评估相应肽和类固醇激素的血浆水平证实了这些数据。α ERKO和β ERKO雌性动物表现出垂体Cga和Lhb表达增加以及血浆LH水平增加，而β ERKO中两者均正常。所有3例ERKO患者的PGEF Fshb表达和血浆FSH均正常。在卵巢中，所有三种ERKO均显示星星、Cyp 11 a和Hsd 3b 1的正常表达。相反，Cyp 17和Cyp 19的表达在alphaERKO中升高，但在betaERKO和alphaERKO中正常。每个ERKO中的血浆类固醇水平反映了类固醇生成酶的表达，只有alphaERKO表现出升高的雄烯二酮和雌二醇。在alphaERKO和AlphaERKO雌性动物中血浆睾酮升高归因于卵巢中Hsd 17 b3的异常表达，这代表了一种内分泌性逆转，因为这种酶是睾丸特有的。用GnRH拮抗剂治疗消除了alphaERKO卵巢中增强的类固醇生成能力，表明这些表型是下丘脑-垂体轴中ER α丢失后过量LH刺激的间接结果。总的来说，这些发现表明ER α，而不是ER β，是必不可少的负反馈效应的雌二醇，保持适当的LH分泌从垂体。随后的性腺功能亢进表现为卵巢中Cyp 17、Cyp 19、Hsd 17 b1和异位Hsd 17 b3表达增加。
To determine the role of each estrogen receptor (ER) form (ERalpha, ERbeta) in mediating the estrogen actions necessary to maintain proper function of the hypothalamic-pituitary-gonadal axis, we have characterized the hypothalamic-pituitary-gonadal axis in female ER knockout (ERKO) mice. Evaluation of pituitary function included gene expression assays for Gnrhr, Cga, Lhb, Fshb, and Prl. Evaluation of ovarian steroidogenic capacity included gene expression assays for the components necessary for estradiol synthesis: i.e. Star, Cyp11a, Cyp17, Cyp19, Hsd3b1, and Hsd17b1. These data were corroborated by assessing plasma levels of the respective peptide and steroid hormones. alphaERKO and alphabetaERKO females exhibited increased pituitary Cga and Lhb expression and increased plasma LH levels, whereas both were normal in betaERKO. Pituitary Fshb expression and plasma FSH were normal in all three ERKOs. In the ovary, all three ERKOs exhibited normal expression of Star, Cyp11a, and Hsd3b1. In contrast, Cyp17 and Cyp19 expression were elevated in alphaERKO but normal in betaERKO and alphabetaERKO. Plasma steroid levels in each ERKO mirrored the steroidogenic enzyme expression, with only the alphaERKO exhibiting elevated androstenedione and estradiol. Elevated plasma testosterone in alphaERKO and alphabetaERKO females was attributable to aberrant expression of Hsd17b3 in the ovary, representing a form of endocrine sex reversal, as this enzyme is unique to the testes. Enhanced steroidogenic capacity in alphaERKO ovaries was erased by treatment with a GnRH antagonist, indicating these phenotypes to be the indirect result of excess LH stimulation that follows the loss of ERalpha in the hypothalamic-pituitary axis. Overall, these findings indicate that ERalpha, but not ERbeta, is indispensable to the negative-feedback effects of estradiol that maintain proper LH secretion from the pituitary. The subsequent hypergonadism is illustrated as increased Cyp17, Cyp19, Hsd17b1, and ectopic Hsd17b3 expression in the ovary.