Context : The expression of androgen receptors ( AR ) in follicular granulosa cells ( GC ) of mammals suggests a role for direct AR - mediated androgen activity in the regulation of folliculogenesis, however this role and the mechanistic pathways involved have not been fully characterised. In women, excess androgen is a characteristic feature of polycystic ovary syndrome ( PCOS ), but AR - mediated activity has not been widely investigated in relation to the pathophysiology of this disorder. Hypotheses : The current thesis tested two general hypotheses related to AR activity in PCOS : 1 ) The polymorphic ( CAG ) n repeat region in the AR gene, which has functional implications for receptor activity, influences the manifestation of PCOS and 2 ) AR signalling is disrupted in GC from women with PCOS. Results : In a cross - sectional population analysis, this thesis reports an association between PCOS and long CAG repeat tracts in the AR gene, which functionally represent reduced androgen sensitivity. The association was further enhanced by compensating for the influence of X chromosome inactivation ( XCI ) on expression of specific AR alleles. Preferential expression of long CAG repeat tracts positively correlated with serum testosterone levels in PCOS patients. In an analysis of sister pairs with the same CAG repeat genotype at the AR locus, different patterns of XCI were evident when sisters had a different clinical manifestation of PCOS. Collectively, these results provide evidence that supports the hypothesis that the ( CAG ) n polymorphism in the AR influences the manifestation of PCOS, the effects of which are modulated by variable allele expression via a mechanism involving XCI. These findings accord with the concept that both genetic and environmental factors are determinants of this disorder. At the level of the ovary, AR - mediated signalling in follicular GC was influenced by proximity to the oocyte in both pigs and humans. In particular, the ability of androgen to directly induce porcine GC proliferation in vitro was dependent upon presence of the oocyte or the oocyte mitogen, growth differentiation 9 ( GDF9 ). This finding provides a potential mechanism to explain how androgens may enhance early follicle growth. Granulosa cells from women with PCOS had normal mRNA expression for AR signalling molecules, but GC surrounding the oocyte in vivo had reduced AR protein content and diminished responses to androgen in culture as compared to those from normal ovaries. GC from women with PCOS also expressed mRNA for an androgen - regulated serine protease ( hKLK3 ), which did not occur in normal GC. Therefore, follicular GC from women with PCOS have evidence of perturbed AR - mediated signalling which is likely to contribute to the pathophysiology of this disorder. As AR - mediated signalling is influenced by the oocyte, the differences in AR - mediated signalling in GC from women with PCOS may be indicative of dysregulated signals emanating from the oocyte. Conclusion : The results of this thesis indicate that abnormal AR action occurs in PCOS, but further investigation is required to determine whether this phenomenon represents a primary disruption or a secondary consequence of another primary disruption in the sequence of events that leads to aberrant folliculogenesis in this disorder. / Thesis (Ph.D.)--School of Paediatrics and Reproductive Health, 2006.

Paclitaxel (PTX) is an effective anti-mitotic drug. It stops cancer from spreading by interfering with the microtubule dynamics which in turn leads to cell cycle arrest and eventually cell death. Despite the clinical success in treating different types of cancers, resistance to PTX remains a major hurdle for successful treatment in relapse patients. Albendazole (ABZ) is a popular anthelmintic used world-wide for the treatment of various types of helmintic infections. In helminthes, ABZ binds to ??-tubulin and inhibits microtubule polymerisation. It was subsequently found that ABZ has anti-cancer activity. This study was carried out to study the effects of ABZ on PTX sensitive and PTX resistant human ovarian carcinoma cells. Cell growth assays revealed that the anti-proliferative activity of ABZ was not only effective on the PTX-sensitive human ovarian carcinoma cell line lA9, but also on its PTX-resistant sub-line, lA9PTX22. The ICso values of ABZ in lA9 and lA9PTX22 were 205 nM and 322 nM, respectively. Confocal images demonstrated that ABZ disrupted the microtubule network and caused formation of short microtubule bundles in both cell lines. Further analysis using tubulin polymerisation assay showed that the percentage of polymerised tubulin in lA9 and lA9PTX22 was increased by 58.9 % and 20.6 % respectively. Together, these results revealed for the first time that ABZ interacts with microtubules in human cancer cells and causes their polymerisation. It was also demonstrated that ABZ increased the release of cytochrome c, an important component of the intrinsic pathway in apoptosis. It was found that the expression of Bim, a BH-3 only pro-apoptotic protein was not elevated after ABZ treatment. The results presented in this study provide some information on the effect of ABZ on the microtubule network which could relate to its apoptotic effect in human ovarian carcinoma cells.

【目的】从整体上把握多囊卵巢综合征的发生、发展及其规律, 为临床进一步诊断治疗提供整体思路和文献学基础。【方法】收集整理近10 年与多囊卵巢综合征研究相关的中、英文献，归纳和总结该病的病因病机、诊断、治疗，找出存在问题，提出发展方向。【结果】①多囊卵巢综合征主要病因为：肾虚、脾虚、肝郁、痰湿、痕血，并与饮食、环境、精神、遗传具有相尖性；②多囊卵巢综合征基本病机：本虚标实，肾虚、脾虚为本’肝郁、气滞、血痕、痰浊、痰湿为标；③PCOS 的分型大致有：肾虚血脐型、肾虚血痕痰浊型；脾肾阳虚型；痕血内阻型；肝气郁结型；脾肾阳虚型；痰湿阻滞型；④PCOS 的治疗以辨证分型论治为主，参考名老中医经验、专方专药、针灸、周期疗法、辨体质进行诊治，重视中西医结合在治疗中的应用。⑤PCOS 仍存在病因、病机认识不一，诊断存在争议’辨证分型众说纷纭等问题。⑥PCOS 发展方向：找出与PCOS 相尖性最强的病因，明确中西医发病机制，规范PCOS 诊断’研发有效药物，加强临床及实验研究，注重基础治疗和健康宣敦。【结论】多囊卵巢综合征的病因、病机、诊断及治疗研究已取得可喜的成绩，形成了完整的体系。但仍存在具体病因不明’发病机制不清，缺乏有效治疗方法等问题。今后应加强高级别基础和临床研究’尽快明确病因病机’找出有效治疗方案。关键词：多囊卵巢综合征；中医；病因病机；证治规律；药物

目的： PCOS 是女性最常见的内分泌疾病, 其症状与并发症严重危害了女性的身心健康。本研究通过收集整体近10 年关于PCOS 的中医临床研究类文献，对本病的证型、治法，尤其是用药处方进行统计、归纳、分析’从而总结出该病的病因病机分布及治疗规律，为PCOS 下一步的临床治疗及用药提供思路和依据。方法：以“多囊卵巢综合征”、“PCOS”、“多囊卵巢”、“不孕症”、“闭经”“中医” 、“中医治疗”、“中医药”等为关键词’搜索2006 年1 月至2016 年12 月刊登在中文学术期刊上有关多囊卵巢综合征中医临床研究类文献，通过建立数据库，对其中医证型及使用方药进行统计分析’归纳总结出多囊卵巢综合征的主要病因病机及治疗用药规律。结果：经过筛选最终得到120 篇文献，共记录病例5670 例，明确治法4616 例，明确证型3778 例。肾虚证型2598 例（ 68. 8% ）；痰湿阻滞型613 例(16. 2%)占84.8% 侨肾3172 例（ 68. 7% ）补肾法中辅以活血化痰之法者也497 例（ 78. 7% ）。药物使用频共中’补虚药（ 43. 7% ）、活血化痕药（ 16.1% ），占59.8% 。归纳的两种疗效评判标准中，总有效率分别为87.9% 、88.9% 。结论： 1. 肾、肝、脾功能失调为PCOS 的发病之源。2. 肾虚、痰湿、血痕是PCOS 的基本病机。3. 补肾健脾，活血化痰是治疗PCOS 的根本大法。4. 补虚药、活血化寐药为治疗PCOS 的主导药物类别。5 中医药治疗PCOS 有副作用小基本黛痛苦璧幢调筒H p O 轴的功能。6. 不同年龄段治疗目的不同导致疗效评判标准尚不统一。关键词：多囊卵巢综合征，中医，用药规律，文献研究

Ovarian cancer is the fifth leading cause of cancer death among women in the U.S. and kills approximately 14,000 women each year (Nezhat et al., 2015). Survival increases with early diagnosis; the five-year survival rate in stage I is 90%. Symptoms are vague and common to many health diseases, which may well explain why upwards of 70% of women with ovarian cancer are diagnosed at stage III or IV (Slatnik & Duff, 2015). Preventative guidelines in the U.S. do not recommend screening for ovarian cancer in women of average risk (AAFP, 2016b; ACOG, 2011; Doubeni et al., 2016; Moyer, 2012; NCCN, 2015; Qaseem et al., 2014; Wilt et al., 2015). A lack of screening recommendations and a subtle presentation point to the need for greater healthcare professional recognition of symptoms and risk factors of ovarian cancer, which can then lead to a prompt diagnosis. While healthcare professionals have the opportunity to improve women’s health, gaps in knowledge exist related to ovarian cancer risk factors and symptom recognition (Gajjar et al., 2012). Continuing education improves healthcare professionals’ performance and patient health outcomes (Cervero & Gaines, 2015). Increasing healthcare professionals’ knowledge of ovarian cancer may help to detect ovarian cancer in earlier stages and enhance health outcomes of women. Based on the need for an increase in awareness and knowledge among healthcare professionals, a local ovarian cancer conference was developed and offered to healthcare professionals. The conference focused on presenting ovarian cancer risk factors and symptoms. Attendees were provided with an ovarian cancer resource for patient education. The conference was evaluated through pretests and posttests and a conference evaluation survey. Data was collected the evening of the conference with 29 attendees responding. After the conference, correct responses increased in the areas of risk factor and symptom recognition. The number of correct responses increased from 106 on the pretest to 122 on the posttest. In regards to ability to educate women about ovarian cancer, 62% of respondents indicated that they were “very confident” in their ability. / Pam Solseng Ovarian Cancer Endowment Fund

published_or_final_version / abstract / toc / Anatomy / Doctoral / Doctor of Philosophy

There is no abstract available for this thesis. / Department of Biology

Indiana University-Purdue University Indianapolis (IUPUI) / Menopausal symptoms, primarily hot flashes, are a pressing clinical problem for both naturally menopausal women and breast and ovarian cancer patients, with a high societal and personal cost. Hot flashes are poorly understood, and animal modeling has been scarce, which has substantially hindered the development of non-hormonal treatments. An emerging factor in the hot flash experience is the role of anxiety and stress-related stimuli, which have repeatedly been shown to influence the bother, frequency, and severity of hot flashes. Causal relationships are difficult to determine in a clinical setting, and the use of animal models offers the ability to elucidate causality and mechanisms. The first part of this work details the development and validation of novel animal models of hot flashes using clinically relevant triggers (i.e., compounds or stimuli that cause hot flashes in clinical settings), which also increase anxiety symptoms. These studies revealed that these triggers elicited strong (7-9 °C) and rapid hot flash-associated increases in tail skin temperature in rats. In a surgical ovariectomy rat model of menopause, which typically exhibit anxiety-like behavior, hot flash provocation revealed an ovariectomy-dependent vulnerability, which was attenuated by estrogen replacement in tested models. An examination of the neural circuitry in response to the most robust flushing compound revealed increased cellular activity in key thermoregulatory and emotionally relevant areas. The orexin neuropeptide system was hyperactive and presented as a novel target; pretreatment with selective and dual orexin receptor antagonists significantly diminished or eliminated, respectively, the response to a hot flash provocation in ovariectomized rats. The insertion/deletion polymorphism of the serotonin transporter has been linked to increased anxiety-associated traits in humans, and subsequent studies prolonged hot flashes in SERT+/- rats, which also caused hot flashes in highly symptomatic women. These studies indicate the orexin system may be a novel non-hormonal treatment target, and future studies will determine the therapeutic importance of orexin receptor antagonists for menopausal symptoms.