Reproductive Endocrinology And Infertility Clinical Training Program

生殖内分泌与不孕不育临床培训项目

• 批准号: 8149304
• 负责人: James H. Segars
• 金额: $ 182.26万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149304
• 关键词: Clinical; Infertility; Reproductive Endocrinology; Training Programs

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 altered mechanical signaling (a method of cell communication and activation) was altered in cells within a fibroid. In the past year we examined the relationship of mechanical signaling of leiomyoma cells in greater detail. 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 determine how the mechanical signaling may be altered (either increased or decreased) in fibroid cells and initiate 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. The goals of this clinical study are to characterize the 1) relationship between chronic pelvic pain, endometriosis, central nervous system sensitization, and myofascial dysfunction, 2) the stress-response, hypothalamic-pituitary-adrenal (HPA) axis and to correlate changes in ACTH and cortisol response with depression and anxiety scores, and 3) relationship between nerves in the endometrium and endometriosis lesions, and chronic pelvic pain. Additionally, in the coming year, in collaboration with NHLBI, we plan to explore markers of progenitor cells in the endometrium of women in order to determine what factors may pre-dispose to implantation of endometrial cells outside of the uterine cavity. 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 concluded studies of a murine model of medical treatment prior to chemotherapy in an effort to explore the mechanisms responsible for preservation of ovarian function with gonadotropin releasing hormone (GnRH) antagonist therapy. We found that pre-treatment of mice with GnRH-antagonist reduced ovarian damage associated with the chemotherapeutic agent, cyclophosphamide. The use of a GnRH antagonist for this purpose has the possible clinical benefit of not causing a flare effect as is observed with GnRH agonist therapy. In the coming year, we plan to examine the mechanism(s) responsible for the protective effect of GnRH-therapy prior to chemotherapy. In addition, we plan to launch a clinical study of ovarian function in pediatric cancer survivors. Infertility and reproductive health disparities Our unit has continued to conduct studies of infertility and reproductive health disparities. In the past year, we have completed a study of reproductive health disparities in women undergoing assisted reproduction treatments. This clinical study indirectly examined the hypothesis that the reduction in pregnancy outcomes observed in African-American women (compared to Caucasian women) are a result of altered endometrial responses possibly due to higher levels of estrogen during the ovarian stimulation. Consistent with that hypothesis, when the endometrium was prepared similarly for embryo transfer, no ethnic differences in pregnancy rates were observed. In the past year, we also examined recruitment and retention issues in clinical trials involving minority women. In the coming year, we plan to examine factors such as cost in utilization of reproductive technologies by minority women. Role of BRX (also known as AKAP13) in cardiac development, immune function and reproduction Our previous studies of the gene BRX, cloned by our group, indicated that this large Rho-GEF protooncoprotein was involved in estrogen and glucocorticoid receptor activation. Furthermore, in a recent collaborative study with Dr. Tomoshige Kino (PRAE) using mice haploinsufficient for BRX, we found that BRX was critical to the response of lymphocytes to osmotic stress through a pathway involving the nuclear factor of activated t-cells 5 (NFAT5) and JIP4. In the past year, we characterized the phenotype of mice deficient for both alleles of the gene (Brx -/- mice). Homozygous mutation of the gene resulted in an embryonic lethal phenotype. Further studies indicated 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). In the coming year we plan to develop a conditional gene targeting strategy using the Cre-Lox system in mice. Use of Gardasil post stem cell transplantation Human papillomavirus (HPV)-associated genital dysplasia, genital graft-versus-host disease and diminished sexual quality of life are all complications that may follow allogeneic hematopoietic stem cell transplantation (HSCT) in women. Our previous studies have shown that up to one-third of female transplant recipients developed HPV-related genital dysplasia. In the current period Dr. Stratton has launched a translational clinical study of the safety and immunogenicity of quadrivalent HPV vaccine (Gardasil) in females over 18 years, as a first step to reduce post-transplant HPV-related co-morbidity. In the coming year, the immune response and outcomes in both female donors and their respective allogeneic, HSCT female recipients will be studied.

子宫肌瘤 到生育年龄结束时，超过 50% 的美国女性会患上子宫肌瘤，使这种疾病成为女性最常见的生殖疾病。尽管这种情况很普遍，但人们对这种情况仍然知之甚少。子宫肌瘤的一个显着特征是肿瘤内的细胞产生紊乱且过多的细胞外基质（ECM）。之前，我们检查了 ECM 以及产生这种过度纤维化 ECM 的细胞的特征，并发现肌瘤内细胞中机械信号传导（一种细胞通讯和激活的方法）发生了改变。在过去的一年中，我们更详细地研究了平滑肌瘤细胞的机械信号传导的关系。此外，我们完成了由博士领导的合作临床试验。 Wood、Stratton 和 Venkatesan 提出了 MRI 引导的高频超声 (HIFU) 用于子宫肌瘤的非手术治疗。来年，我们计划确定肌瘤细胞中的机械信号如何改变（增加或减少），并启动第二项高强度聚焦超声非手术治疗子宫肌瘤的研究。 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和子宫内膜异位症的关联。这项由 Stratton 博士领导的正在进行的临床研究在三组女性中检查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、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。本临床研究的目标是表征 1) 慢性盆腔疼痛、子宫内膜异位症、中枢神经系统敏化和肌筋膜功能障碍之间的关系，2) 应激反应、下丘脑-垂体-肾上腺 (HPA) 轴，并将 ACTH 和皮质醇反应的变化与抑郁和焦虑评分相关联，以及 3) 子宫内膜神经与子宫内膜异位症之间的关系 病变和慢性盆腔疼痛。此外，在来年，我们计划与 NHLBI 合作，探索女性子宫内膜中的祖细胞标记，以确定哪些因素可能导致子宫内膜细胞在子宫腔外植入。 接受癌症治疗的妇女和年轻女孩卵巢功能的评估和保存 由于癌症生存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损害。去年，我们完成了化疗前药物治疗小鼠模型的研究，旨在探索促性腺激素释放激素 (GnRH) 拮抗剂治疗保护卵巢功能的机制。我们发现用 GnRH 拮抗剂预先治疗小鼠可减少与化疗药物环磷酰胺相关的卵巢损伤。为此目的使用 GnRH 拮抗剂具有可能的临床益处，即不会引起用 GnRH 激动剂治疗观察到的耀斑效应。来年，我们计划研究化疗前 GnRH 疗法的保护作用机制。此外，我们计划开展一项儿童癌症幸存者卵巢功能的临床研究。 不孕不育和生殖健康差异 我们单位继续对不孕不育和生殖健康差异进行研究。去年，我们完成了一项关于接受辅助生殖治疗的女性生殖健康差异的研究。这项临床研究间接检验了以下假设：非洲裔美国女性（与白人女性相比）妊娠结局的减少是由于卵巢刺激期间雌激素水平较高而导致子宫内膜反应改变的结果。与该假设一致，当子宫内膜经过类似的准备用于胚胎移植时，没有观察到妊娠率的种族差异。去年，我们还研究了涉及少数族裔女性的临床试验中的招募和保留问题。来年，我们计划研究少数民族妇女使用生殖技术的成本等因素。 BRX（也称为 AKAP13）在心脏发育、免疫功能和生殖中的作用 我们之前对我们小组克隆的 BRX 基因的研究表明，这种大的 Rho-GEF 原癌蛋白参与雌激素和糖皮质激素受体的激活。此外，在最近与 Tomoshige Kino 博士 (PRAE) 合作使用 BRX 单倍体不足的小鼠进行的一项合作研究中，我们发现 BRX 通过涉及活化 t 细胞核因子 5 (NFAT5) 和 JIP4 的途径对淋巴细胞对渗透应激的反应至关重要。在过去的一年中，我们对缺乏该基因的两个等位基因的小鼠（Brx -/- 小鼠）的表型进行了表征。该基因的纯合突变导致胚胎致死表型。进一步的研究表明，BRX 基因产物通过小鼠心肌细胞发育中的重要转录程序（涉及肌细胞增强因子 2 C (MEF2C)）协调 G-sub-alpha-s 和 Rho 信号传导。来年，我们计划在小鼠中使用 Cre-Lox 系统开发一种条件基因靶向策略。 干细胞移植后使用 Gardasil 人乳头瘤病毒（HPV）相关的生殖器发育不良、生殖器移植物抗宿主病和性生活质量下降都是女性异基因造血干细胞移植（HSCT）后可能出现的并发症。我们之前的研究表明，多达三分之一的女性移植受者患有 HPV 相关的生殖器发育不良。目前，Stratton 博士启动了一项针对 18 岁以上女性的四价 HPV 疫苗 (Gardasil) 安全性和免疫原性的转化临床研究，作为减少移植后 HPV 相关并发症的第一步。来年，我们将研究女性捐赠者及其各自的同种异体造血干细胞移植女性接受者的免疫反应和结果。

项目成果

Keeping clinicians in clinical research: the Clinical Research/Reproductive Scientist Training Program.

• DOI: 10.1016/j.fertnstert.2008.10.029
• 发表时间: 2009-03
• 期刊: Fertility and sterility
• 影响因子: 6.7
• 作者: Armstrong AY;Decherney A;Leppert P;Rebar R;Maddox YT
• 通讯作者: Maddox YT

Reproductive impact of MRI-guided focused ultrasound surgery for fibroids: a systematic review of the evidence.

• DOI: 10.1097/gco.0000000000000070
• 发表时间: 2014-06
• 期刊: Current opinion in obstetrics & gynecology
• 影响因子: 2.1
• 作者: Clark NA;Mumford SL;Segars JH
• 通讯作者: Segars JH

Racial and ethnic disparities in assisted reproductive technology outcomes in the United States.

• DOI: 10.1016/j.fertnstert.2008.10.061
• 发表时间: 2010-02
• 期刊: Fertility and sterility
• 影响因子: 6.7
• 作者: Fujimoto VY;Luke B;Brown MB;Jain T;Armstrong A;Grainger DA;Hornstein MD;Society for Assisted Reproductive Technology Writing Group
• 通讯作者: Society for Assisted Reproductive Technology Writing Group

Imprinting disorders and assisted reproductive technology.

• DOI: 10.1016/j.fertnstert.2009.01.002
• 发表时间: 2009-02
• 期刊: Fertility and sterility
• 影响因子: 6.7
• 作者: Manipalviratn S;DeCherney A;Segars J
• 通讯作者: Segars J

The role of adiponectin in reproduction: from polycystic ovary syndrome to assisted reproduction.

• DOI: 10.1016/j.fertnstert.2010.05.010
• 发表时间: 2010-11
• 期刊: FERTILITY AND STERILITY
• 影响因子: 6.7
• 作者: Michalakis, Konstantinos G.;Segars, James H.
• 通讯作者: Segars, James H.