Hyperprolactinemia in a male pituitary androgen receptor knockout mouse is associated with female-like lactotroph development.
Hyperprolactinemia in a male pituitary androgen receptor knockout mouse is associated with female-like lactotroph development.
复制标题
雄性垂体雄激素受体敲除小鼠的高催乳素血症与雌性催乳素发育相关。
作者：
O'Hara L
背景：啮齿动物和人类的循环催乳素浓度是两性二态的。雌激素是一种特性良好的催乳素释放刺激物。在整个女性月经/发情周期中，循环催乳素随着雌激素水平的变化而波动，但在男性中却持续处于低水平。我们之前已经通过对具有条件垂体雄激素受体敲除（PARKO）的雄性小鼠的特征鉴定，确定雄激素是催乳素释放的抑制剂，其循环催乳素增加，但乳营养细胞数量不变。目的研究雄激素抑制催乳素释放的作用细胞类型。材料和方法采用催乳素ELISA、垂体电镜、免疫组织化学和qRT - PCR对sparko、乳营养蛋白特异性、Pit1谱系特异性和神经特异性条件雄激素受体敲除雄性小鼠进行研究。结果嗜乳细胞特异性、Pit1谱系特异性和神经特异性条件AR敲除不会复制PARKO系中所见的高循环催乳素。利用电子显微镜检查超微结构，我们发现垂体雄激素受体敲除的雄性小鼠产生了与雌性小鼠相似的乳营养物质。与完整的雄性相比，阉割的PARKO雄性的循环催乳素明显减少。当检测选定的雌激素调节的垂体前叶基因的表达时，对照组和敲除组之间的表达水平没有差异。雄激素作用于抑制催乳素释放的细胞类型不是乳营养细胞、Pit1谱系细胞或下丘脑的多巴胺能神经元。PARKO雄性会形成雌性特有的嗜乳细胞超微结构，这可能会导致循环催乳素的增加。与完整的雄性相比，阉割的PARKO雄性的循环催乳素明显减少，这表明去除循环雌激素和雄激素会减少垂体催乳素释放的刺激。结论雌激素-雄激素平衡的变化对催乳素的调节作用，可能与发育过程中的两性异形和高泌乳素血症等疾病有关，有待进一步研究。
BackgroundCirculating prolactin concentration in rodents and humans is sexually dimorphic. Oestrogens are a well‐characterised stimulator of prolactin release. Circulating prolactin fluctuates throughout the menstrual/oestrous cycle of females in response to oestrogen levels, but remains continually low in males. We have previously identified androgens as an inhibitor of prolactin release through characterisation of males of a mouse line with a conditional pituitary androgen receptor knockout (PARKO) which have an increase in circulating prolactin, but unchanged lactotroph number.ObjectivesIn the present study, we aimed to specify the cell type that androgens act on to repress prolactin release.Materials and methodsPARKO, lactotroph‐specific, Pit1 lineage‐specific and neural‐specific conditional androgen receptor knockout male mice were investigated using prolactin ELISA, pituitary electron microscopy, immunohistochemistry and qRT‐PCR.ResultsLactotroph‐specific, Pit1 lineage‐specific and neural‐specific conditional AR knockouts did not duplicate the high circulating prolactin seen in the PARKO line. Using electron microscopy to examine ultrastructure, we showed that pituitary androgen receptor knockout male mice develop lactotrophs that resemble those seen in female mice. Castrated PARKO males have significantly reduced circulating prolactin compared to intact males. When expression of selected oestrogen‐regulated anterior pituitary genes was examined, there were no differences in expression level between controls and knockouts.DiscussionThe cell type that androgens act on to repress prolactin release is not the lactotroph, cells in the Pit1‐lineage, or the dopaminergic neurons in the hypothalamus. PARKO males develop a female‐specific lactotroph ultrastructure that this is likely to contribute to the increase in circulating prolactin. Castrated PARKO males have significantly reduced circulating prolactin compared to intact males, which suggests that removal of both circulating oestrogens and androgens reduces the stimulation of pituitary prolactin release.ConclusionFurther investigation is needed into prolactin regulation by changes in androgen‐oestrogen balance, which is involved sexual dimorphism of development and diseases including hyperprolactinemia.