Anterior Pituitary Gland in Female Reproductive Aging

女性的生殖衰老是通过卵巢配子发生和类固醇合成的进行性下降来确定的。在动物模型和人类中的研究表明，除了卵巢衰竭外，这种下降可能是由于与年龄有关的生殖轴下丘脑-垂体水平的功能障碍。为了了解导致生殖功能丧失的机制，研究人员越来越多地将重点放在永久无周期建立之前的时期(即，发生在妇女生命的第五个十年期间或实验室动物的同等阶段)。这些研究清楚地记录了与年龄相关的垂体促性腺激素基因表达的紊乱；然而，目前尚不清楚这些变化是否反映了已知的 下丘脑促性腺激素释放激素(GnRH)的刺激或额外原因是原发性垂体促性腺激素功能障碍。本研究旨在利用去卵巢、激素替代的雌性大鼠模型，阐明垂体前叶在雌性生殖衰老发育中的作用。该模型消除了由于不同年龄的循环性腺类固醇水平的差异造成的混杂效应。其具体目的是：1)确定已知与正常促性腺功能相关的基因在垂体中表达的年龄相关变化，以及2)比较GnRH刺激的促性腺激素和GnRH受体基因在灌流液中的表达。 幼年和中年雌性大鼠的脑垂体前叶。初步实验已经证明，在中年动物的黄体生成素高峰当天，促性腺激素和促性腺激素释放激素受体基因的表达减弱。在SA#I中，这些观察将扩展到对其他促性腺激素相关基因的分析，包括：a)性腺类固醇受体，b)激活素、抑制素和卵泡抑素，以及c)垂体腺苷环化酶激活肽(PACAP)。在SA#2中，与年龄相关的促性腺激素特异基因表达的变化将表现为对相同的脉冲式GnRH治疗的反应，从而能够检测出与下丘脑功能障碍不同的固有垂体缺陷。这些研究将进一步深入了解导致女性生殖老化的分子和细胞机制。 并因此将提高我们对生命这个阶段的影响的理解。

Reproductive aging in the female is identified by a progressive decline in ovarian gametogenesis and steroidogenesis. Investigations in animal models and in humans suggest that, in addition to ovarian failure, this decline may be attributable to age-related dysfunction at the hypothalamic-pituitary level of the reproductive axis. In order to understand the mechanisms which lead to the loss of reproductive function, investigators have increasingly focused on the period just preceding the establishment of permanent acyclicity (ie., events that occur during the fifth decade of life in women or the equivalent stage in laboratory animals). These studies have clearly documented age-related perturbations in pituitary gonadotropin gene expression; however, it is not known currently whether these changes reflect known alterations in hypothalamic gonadotropin-releasing hormone (GnRH) stimulation or are due additionally to primary dysfunction of the pituitary gonadotropes. The proposed studies are aimed at elucidation of the role of the anterior pituitary gland in the development of reproductive senescense in the female, utilizing an ovariectomized, steroid-replaced female rat model. This model eliminates confounding effects due to age-specific differences in circulating gonadal steroid levels. The Specific Aims are: 1) to identify age-related changes in pituitary expression of genes with known relevance for normal gonadotrope function, and 2) to compare GnRH-stimulated expression of gonadotropin and GnRH-receptor gene expression in perifused anterior pituitaries from young and middle-aged female rats. Preliminary experiments have demonstrated blunted expression of the gonadotropin and GnRH-receptor genes on the day of the LH surge in middle-aged animals. In SA#I, these observations will be extended to the analysis of additional gonadotrope-relevant genes, including: a) gonadal steroid receptors, b) activin, inhibin, and follistatin, and c) pituitary adenylate-cyclase activating peptide (PACAP). In SA#2, age-related alterations in gonadotrope-specific gene expression will be characterized in response to identical pulsatile GnRH treatment, enabling the detection of intrinsic pituitary defects distinct from hypothalamic dysfunction. These studies will provide additional insight into the molecular and cellular mechanisms which contribute to female reproductive aging and will, thereby, improve our understanding of the repercussions of this stage of life.