Adrenal Axis and the Reproductive Process

我们的总体目标是研究应激，以及激活的下丘脑-垂体-肾上腺轴（HPA），如何改变下丘脑-垂体-性腺轴（HPG）的正常功能，并干扰相关非人灵长类动物的正常月经周期。在之前的资助期内，我们在恒河猴身上开发了两种不同的短期应激模型（炎症性和心因性），并证明它们确实会干扰正常的循环功能，诱导周期阶段和应激特异性损伤，其中可能包括卵泡发育延迟，黄体分泌能力下降，使人回忆起黄体期不足综合征，和/或干扰正常的促性腺激素水平。前两个目的将研究两种主要的HPA神经肽CRH和抗利尿激素（VP）在应激干扰月经周期过程中的作用，通过它们的中枢释放和特异性CRH和VP拮抗剂的作用来中和内源性HPA活性。由于不同的应激可能激活不同的中枢通路，而中枢通路可能对卵巢类固醇具有不同的敏感性，因此我们将比较HPA和HPG在两种不同应激模型以及卵泡期和黄体期的作用。目的3的目标是发展一个长期的压力，导致闭经，确定临床功能性下丘脑慢性无排卵综合征的定义症状。在这里，我们将测试两种不相关的刺激，如心因性应激和饮食，是否可以协同产生综合征，并研究CRH、VP和阿片肽在确定的闭经中的作用。我们还将研究瘦素作为应激相关内分泌功能和生殖调节的新角色是否对闭经起保护作用。总的来说，这些数据将有助于我们理解不同应激刺激干扰生殖功能的不同机制，以及卵巢内分泌环境如何影响这一过程。他们将提供关于早期阶段的新信息，即压力不足以中断周期，干扰正常的周期功能并可能导致不孕，并为慢性无排卵综合征的治疗开辟新的途径。

Our overall objective is to investigate how stress, and by definition an activated hypothalamic-pituitary-adrenal axis (HPA), acts to modify normal function of the hypothalamic- pituitary-gonadal axis (HPG) and to interfere with the normal menstrual cycle in a relevant non-human primate. In the previous funding period, we developed two distinct short-term stress models (inflammatory and psychogenic) in the rhesus monkey and demonstrated that they reliably interfere with normal cyclic function and induce cycle stage- and stress-specific damage that may include a delay in folliculogenesis, a decrease in luteal secretory capability reminiscent of the inadequate luteal phase syndrome, and/or interference with the normal tonic gonadotropin profile. The first two aims will investigate the role of the 2 main HPA neuropeptides, CRH and vasopressin (VP), in the process by which stress interferes with the menstrual cycle by correlating their central release and the effects of specific CRH and VP antagonists to neutralize endogenous HPA activity. Since different stress may activate varying central pathways, which may, in turn, have different sensitivities to ovarian steroids, we will compare HPA and HPG effects in the 2 different stress models and in the follicular and luteal phase of the cycle. The goal of aim 3 is to develop a long-term stress that results in amenorrhea, the defining symptom of the established clinical functional hypothalamic chronic anovulation syndrome. Here, we will test whether two unrelated stimuli, such as a psychogenic stress and diet, can synergize to produce the syndrome and investigate the role of CRH, VP and opioid peptides in established amenorrhea. We will also investigate whether leptin, in a new role as a modulator of stress-related endocrine function and reproduction, plays a protective role against amenorrhea. Overall, the data will contribute to our understanding of the varying mechanisms whereby different stress stimuli interfere with reproductive function and of how the ovarian endocrine milieu influences this process. They will provide novel information on the early stages whereby a stress, insufficient to interrupt the cycle, interferes with normal cyclic function and may result in infertility, and open new avenues of treatment in the chronic anovulation syndrome.