Reproductive Endocrinology And Infertility Clinical Training Program

子宫肌瘤 在美国，超过50%的女性在生育年龄结束时会患上子宫肌瘤，这使这种疾病成为女性中最常见的生殖障碍。尽管这种情况很普遍，但人们对这种情况仍然知之甚少。子宫肌瘤的一个显著特征是肿瘤内的细胞产生无序和过度的细胞外基质(ECM)。以前，我们已经检查了细胞外基质和产生这种过度和纤维化的细胞外基质的细胞特征，并发现在肌瘤内的细胞中，机械信号(一种细胞沟通和激活的方法)发生了变化。在过去的一年里，我们发现构成肌瘤的细胞对机械刺激的反应减弱(降低)。此外，我们完成了由MRI引导的高频超声(HIFU)的Wood、Stratton和Venkatesan博士领导的非手术治疗子宫肌瘤的合作临床试验。在接下来的一年里，我们计划用HIFU开始第二项研究，用于子宫肌瘤的非手术治疗。 慢性盆腔疼痛和子宫内膜异位症 我们继续研究慢性盆腔疼痛与子宫内膜异位症的关系。斯特拉顿博士领导的这项正在进行的临床研究在三组女性中检验了慢性盆腔疼痛和子宫内膜异位症之间的关系：患有慢性疼痛和子宫内膜异位症的女性，那些患有慢性盆腔疼痛但没有子宫内膜异位症证据的女性，以及健康志愿者。慢性盆腔疼痛与子宫内膜异位症有关，但我们发现，在一组子宫内膜异位症患者中，浅表病变的位置与疼痛位置无关。我们还发现，患有慢性盆腔疼痛的女性中有三分之二患有偏头痛，这一发现独立于子宫内膜异位症。这些发现表明，与子宫内膜异位症相关的慢性盆腔疼痛可能是中枢神经系统敏感化和肌筋膜功能障碍的结果。 接受癌症治疗的妇女和年轻女孩的卵巢功能评估和保存 由于癌症存活率的提高和有效的化疗，许多年轻女孩和妇女现在能够在癌症中存活下来，但发现生殖功能受到了损害。在过去的一年里，我们已经完成了动物和临床研究，计划继续在儿科临床人群中进行更多的研究，并进行更多的动物研究，以探讨在接触烷化剂后原始卵泡保存的可能机制(S)。我们还将继续我们对不孕症患者卵巢储备减少的研究。在过去的一年里，我们报道了动物数据，表明GnRH类似物在暴露于化疗药物环磷酰胺后保留了原始毛囊。结果表明，这可能是由于细胞凋亡(程序性细胞死亡)的减少。在未来一年，我们计划调查可能涉及的机制(S)。我们还计划开始一项临床研究，在这一患者群体中检查卵巢储备的新生物标志物。 不孕不育和生殖健康差距 我们单位继续进行不孕不育和生殖健康差距的研究。阿姆斯特朗博士帮助建立了一个关于健康差距专题的特别利益小组和国家研究网络。该分会的研究人员帮助在美国生殖医学会年会上安排了一次关于生殖健康差异的新的摘要会议。在过去的一年里，阿姆斯特朗博士还主持了一次由NICHD主办的关于健康差距的会议。在未来一年，计划启动一个项目，检查暴露在环境生殖毒素中的种族和种族差异。 BRX(又称AKAP13)在心脏发育、免疫功能和生殖中的作用 我们以前对本课题组克隆的BRX(AKAP13)基因的研究表明，这个大的Rho-egf原癌蛋白参与了雌激素和糖皮质激素受体的激活。我们先前发现，BRX基因产物在小鼠心肌细胞发育过程中协调G-亚α-S和Rho信号与一个必要的转录程序，涉及心肌细胞增强因子2C(MEF2C)。带有两个AKAP13基因缺陷拷贝(敲除)的小鼠在子宫中死亡。在过去的一年里，我们在利用Cre-Lox系统在小鼠身上开发条件基因靶向策略方面取得了进展。计划是检查有条件的目标后代的表型。此外，在接下来的一年里，我们将检查AKAP13零等位基因杂合子小鼠的表型，以确定这些小鼠是否在雌激素或糖皮质激素信号方面存在微妙的异常。

Uterine leiomyoma By the end of their reproductive years, over 50% of women in the United States develop uterine fibroids, making the condition the most prevalent reproductive disorder of women. Despite their prevalence, the condition remains poorly understood. One prominent feature of uterine fibroids is that cells within the tumors produce a disordered and excessive extracellular matrix (ECM). Previously, we have examined the ECM and characteristics of the cells that produce this excessive and fibrotic ECM and have found that mechanical signaling (a method of cell communication and activation) was altered in cells within a fibroid. In the past year we have found that cells that comprise a fibroid have impaired responses (decreased) to mechanical stimuli. Additionally, we completed a collaborative clinical trial led by Drs. Wood, Stratton and Venkatesan of MRI-guided high frequency ultrasound (HIFU) for the non-surgical treatment of uterine fibroids. In the coming year we plan to begin a second study with HIFU for the non-surgical treatment of uterine fibroids. Chronic Pelvic Pain and Endometriosis We have continued to investigate the association of chronic pelvic pain and endometriosis. This ongoing clinical study led by Dr. Stratton examines the relationship between chronic pelvic pain and endometriosis in three cohorts of women: women with chronic pain and endometriosis, those with chronic pelvic pain but no evidence of endometriosis, and healthy volunteers. Chronic pelvic pain is associated with endometriosis, but we have found that the location of superficial lesions does not correlate with pain location in a cohort of women with endometriosis. We also have found that two thirds of women with chronic pelvic pain have migraine headaches, a finding independent of endometriosis. These findings suggest that chronic pelvic pain associated with endometriosis is likely the result of central nervous system sensitization and myofascial dysfunction. Assessment and preservation of ovarian function in women and young girls undergoing cancer treatment Because of improved survival and effective chemotherapy for cancers, many young girls and women now are able to survive cancer, but find that reproductive function is impaired. In the past year we have completed animal and clinical investigations with plans to continue additional studies in a pediatric clinical populations and additional animal studies to examine potential mechanism(s) for preservation of primordial follicles after exposure to alkylating agents. We will also continue our study of diminished ovarian reserve in infertility patients. In the past year we reported animal data that suggested GnRH analogues preserve primordial follicles after exposure to the chemotherapy agent, cyclophosphamide. Results suggested that this may be due to a decrease in apoptosis (programmed cell death). In the coming year, we plan to investigate possible mechanism(s) involved. We also plan to begin a clinical study to examine new biomarkers of ovarian reserve in this patient population. Infertility and reproductive health disparities Our unit has continued to conduct studies of infertility and reproductive health disparities. Dr. Armstrong helped to established a Special Interest Group and national research network on the topic of Health Disparities. Investigators in the branch helped to arrange the a new abstract session at the Annual Meeting of the American Society of Reproductive Medicine on this reproductive health disparities. In the past year, Dr. Armstrong also led an NICHD-hosted conference on Health Disparities. In the coming year, the plans are to initiate a project to examine ethnic and racial differences in exposure to environmental reproductive toxins. Role of BRX (also known as AKAP13) in cardiac development, immune function and reproduction Our previous studies of the gene BRX (AKAP13), cloned by our group, indicated that this large Rho-GEF protooncoprotein was involved in estrogen and glucocorticoid receptor activation. We previously found that the BRX gene product coordinates G-sub-alpha-s and Rho signaling with an essential transcription program in developing cardiomyocytes in mice, involving myocyte enhancer factor 2 C (MEF2C). Mice with two defective copies of the AKAP13 gene (knockout) died in utero. In the past year we have made progress on development of a conditional gene targeting strategy using the Cre-Lox system in mice. Plans are to examine the phenotypes of the conditionally-targeted offspring. In addition, in the coming year we will examine the phenotypes of mice heterozygous for the AKAP13 null allele to determine whether these mice may have subtle abnormalities in estrogen or glucocorticoid signaling.