M.A. / In this study an attempt is made to understand the phenomenological experience of women in spontaneous premature menopause. There is very little literature available about spontaneous premature menopause and even less about the experiences of women in spontaneous premature menopause. Spontaneous premature menopause is viewed as a negative experience in the woman’s life and medical staff recommend that she should receive treatment for spontaneous premature menopause. In this study the woman, herself, was asked how she feels about spontaneous premature menopause and how it affects her life. Phenomenological research procedures are used in this study. Interviews were conducted with three participants. They were asked to tell the researcher about their experience of spontaneous premature menopause and how it affected their lives. Hermeneutic phenomenology is used to analyse the participants’ experience of spontaneous premature menopause. Themes and categories that stood out during analyses are discussed and interpreted. Results of the study show that spontaneous premature menopause can cause bodily changes in women; it can lead to several different menopausal symptoms and it can have a negative effect on her relationship with her family, friends and other people. Bodily changes that can occur, because of spontaneous premature menopause include weight gain, changes in the breasts, changes to the vagina, skin changes, bladder changes, itchy skin, heart palpitations and changes to the pelvic floor. Symptoms that can occur during spontaneous premature menopause include hot flushes, night sweats, headaches, sleep difficulties, tiredness, depression, forgetfulness, mixed emotions and pain in different areas of the body. Participants felt that their bodies, their doctors and their family and friends failed them. They had no one to turn to, because significant people in their lives did not believe that they are in spontaneous premature menopause. They were told that it must be something else like depression. The participants had shock reactions due to feelings of loss. They no longer had the body of a young woman. They had lost their youthful appearance, their sexuality, their abilty to bear children and to function satisfactorily in their daily duties. These women had to come to grips with the fact that their youthful days were over and that they were aging before their time. It is suggested that cross-cultural research be done in the future to establish how women in other cultures experience spontaneous premature menopause. Comparisions can be made and if there are any differences efforts can be made to establish what causes these differences. Cultures where spontaneous premature menopause is viewed as a positive event in a woman’s life can be researched to establish how this experience can be turned into a positive experience in cultures where it is viewed negatively.

目的：收集及整理近5 年有失治疗卵巢早衰的中医和中西医结合文献，对该病的病因病机、治疗原则和方法，以及中医处方用药及临床疗效进行统计分析、归纳及总结，探寻卵巢早衷的证治方法和用药规律’为今后的中医药治疗提供系统化思路和文献学基础。方法：对收集到的符合标准的85 篇文献进行病因病机、证治方药和臨床疗效的归纳，并用Excel 软件建立数据库并进行数据统计分析。结果：通过对85 篇文献分析’卵巢早衰常见病因病机共有11 大类：肾精亏虚、肾虚肝郁、括子血阻滞、肾阳虚、肾阴虚、脾肾两虚、肝肾阴虚、气血不足、心肾不交、痰湿阻滞、以及其他。肾精亏虚所占比例最大，为29.26% 。将与“肾虚”相关的所有病机一起合计，所占比例为75.58% 。治疗药物出现总体频次为1292 味次，其中居第一位为补益药，共849 味矢，占65.71% ；居第二、第二位的分别为活血桔痕药， 165 味女，占12.77% ；清热药， 66 味矢，占5.11% 。高频药物：熟地、当归、莞丝子、山药、山英肉、构丰己子。结论：肾虚是卵巢早衰发病的根本病因病机，肝郁气滞和膝阻；中任是发病的主要环节。提出临床治疗该病的基本思路与方法为： (1 ）补肾为玉，佐以疏肝养肝、健脾养心是治本之法；（ 2 ）标本兼治，活血化插手是卵巢早衰主要的治标之法；（ 3)滋阴柔肝、清热凉血也是卵巢早衰常用的治疗方法之一；（ 4 ）中药周期疗法和辨证论治相结合；（ 5 ）身心同治，配合心理疏导。關键词：卵巢早衰；中医药治疗卵巢早衰；现代临床文献研究；病因病机；证治方药

Kidney disease is a major complication of diabetes and accounts for one-third of all diabetes-related deaths. Estrogen is considered protective against cardiovascular and non-diabetic renal disease, however it is unclear if this protection extends to diabetes and diabetic kidney disease.To address these questions, we have used a new model of menopause in which repeated daily injections of 4-vinylcyclohexene (VCD) induces gradual ovarian failure in mice. Unlike with ovariectomy, the VCD model preserves the gradual transition into ovarian failure (OF) (modeling perimenopause). Also, following OF, the residual ovarian tissue is retained and secretes androgens, similar to the androgen production by postmenopausal human ovaries.The VCD model of menopause was combined with the streptozotocin (STZ) model of type 1 diabetes, and the development of diabetes and diabetic kidney damage were studied over the subsequent 6 weeks. We observed that blood glucose levels are higher in post-OF diabetic mice compared to cycling diabetic and peri-OF diabetic mice. Renal cell proliferation, an early marker of kidney damage, is increased in post-OF diabetic mice compared to cycling diabetic mice, as measured by expression of proliferating cell nuclear antigen. We also demonstrate that expression of α-smooth muscle actin is increased in post-OF diabetic mice compared to cycling diabetic mice. Five weeks after STZ injection, post-OF diabetic mice had higher rates of urine albumin excretion than cycling diabetic mice.Using real-time PCR, we identified changes in expression between post-OF diabetic and cycling diabetic mice of genes which have previously been associated with diabetic kidney damage. We also show that some of these changes occur in peri-OF diabetic mice as well. Using microarray, we identified 119 new genes which are regulated by the combination of ovarian failure and diabetes in the mouse kidney.These data support our hypothesis that the changes in hormones which occur during the transition into ovarian failure exacerbate the development and progression of diabetic kidney damage in mice. These data also highlight the utility and importance of the VCD model of menopause in the study of diabetic kidney damage.

OBJECTIVE: Premature ovarian failure is a disease with many far reaching and serious consequences. Little is known about the complete etiology of the disease or what women may be at an increased risk for developing it. We sought to evaluate the prevalence of premature ovarian failure among women born in the United States and women not born in the United States who were patients of Boston Medical Center. We compared the prevalence of POF in these two groups to evaluate any relationships that may exist between birthplace and premature ovarian failure. METHODS: We collected data from the data warehouse of Boston Medical Center. We used data from women who had an FSH test done between the ages of 18 and 40 before June 30, 2013 as the control. We also compiled data of women who had an FSH level over 15mIU/ml as well as those who had diagnoses in SDK and Logician. Birthplaces data was also compiled for those women who had an FSH level>15mIU/ml. RESULTS: Women born outside of the U.S had a slightly higher prevalence of POF when compared to women born in the United States. Data analysis showed a significant difference among the two groups with p<0.0001 for each group. When birthplace data was compiled, Haiti had the highest number of women with FSH>15mIU/ml with Cape Verde and the Dominican Republic having the next highest amounts of women. CONCLUSION: Our study highlights the possible relationship that exists between premature ovarian failure and birthplace. This was a preliminary study to gather data that may be used in future, more specific studies to be done on the topic. These future studies should further investigate the reason this relationship exists, other causes that may be associated with premature ovarian failure, and further analysis of the prevalence of POF in various areas of the world.

Chemotherapy treatment in premenopausal women has been linked to premature ovarian failure (POF), and hence infertility, through ovarian follicle loss. The exact mechanisms that lie behind this loss are unclear and so the action of two commonly used chemotherapeutic agents were compared here. Cisplatin is a DNA cross-linking agent commonly used in the treatment of ovarian, lung and bladder cancers, while the anthracycline doxorubicin is commonly used to treat leukaemia and breast cancer. Neonatal mouse ovaries were cultured in vitro and exposed to cisplatin or doxorubicin in order to determine their effects on primordial and early growing follicles. Both drugs caused a dose dependant follicle loss but targeted different cell types. Cisplatin caused a significant increase in follicles with unhealthy oocytes; furthermore primary stage follicles were the follicle class most affected (up to 98% classified as unhealthy compared with 13% in control, p<0.001). In contrast, doxorubicin caused a significant increase in follicles with unhealthy granulosa cells and affected all follicle stages present. When the mechanism of cell death was further investigated, apoptosis was the main pathway through which these drugs cause ovarian cell death. Doxorubicin in particular caused a significant increase in apoptosis of ovarian somatic cells including the granulosa cells and stroma. Imatinib mesylate, a tyrosine kinase inhibitor which is also used as a chemotherapeutic agent, has been implicated as a potential therapy to block the ovotoxic effects of cisplatin. Results here confirm this finding (29% of follicles classified as unhealthy in the cisplatin only group compared to 8% in the cisplatin and imatinib co-treatment group, p<0.001) and found further, that imatinib was unable to protect against doxorubicin-induced damage (28% of follicles classified as unhealthy in the doxorubicin treated group compared to 19% in the doxorubicin and imatinib cotreatment group). Imatinib treatment alone in newborn ovaries caused a significant increase in the number of follicles present at the end of culture compared to control (402±43 in the imatinib group compared to 188±34 in control, p<0.001), which is likely due to an effect on follicle formation. In conclusion, the work presented in this thesis demonstrates drug specific actions of cisplatin and doxorubicin on the mouse ovary. This suggests that any therapy designed to confer ovarian protection in the future may have to be tailored to be drug specific.

Thesis (Ph. D.)--University of Missouri-Columbia, 1997. / Typescript. Vita. Includes bibliographical references (leaves 130-145). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 1997. / Typescript. Vita. Includes bibliographical references (leaves 130-145). Also available on the Internet.

O câncer de mama (CM) é o segundo tipo de câncer mais comum no mundo. Sabe-se que a maior incidência de CM ocorre nas mulheres pós-menopausa, entretanto é crescente o número de mulheres jovens acometidas por esta doença. O tratamento do CM pode incluir: quimioterapia, radioterapia e/ou hormonioterapia. A quimioterapia, por se ser um tratamento sistêmico, pode causar importantes efeitos colaterais, entre eles a falência ovariana induzida por quimioterapia (FOIQ). As principais consequências da FOIQ são a infertilidade, além de complicações tardias relacionadas à diminuição do estrogênio, como a osteoporose e doenças cardiovasculares. O regime quimioterápico TC, adota a associação do docetaxel com a ciclofosfamida, como uma opção por fármacos que resultem numa taxa de sobrevida livre do câncer, e menores efeitos colaterais. Este trabalho teve como objetivo estudar os efeitos tardios no ovário causados pelo tratamento com a associação dos quimioterápicos docetaxel e ciclofosfamida (TC), em modelo animal com ratos Wistar. Para verificar o sinergismo desses quimioterápicos e assim analisar o efeito da administração conjunta, ratos Wistar fêmeas foram divididos em dois grupos: um grupo controle e um grupo que recebeu quimioterapia (TC). Os animais foram submetidos a eutanasia cinco meses após o fim do tratamento, e foram recolhidos o plasma e os ovários. Foram observadas alterações importantes. O nível de estradiol no plasma foi significativamente reduzido no grupo de TC em comparação com o grupo controle. Além disso, o número de núcleos apoptóticos foi maior no grupo TC. O papel da resposta inflamatória no desenvolvimento da lesão ovariana foi também investigado, e notou-se um aumento do número de mastócitos, e aumento da expressão de Fator de Necrose Tumoral-&#945; (TNF-&#945;) no grupo TC. O envolvimento de fibrose nesse processo, foi também investigado. Os resultados mostraram que níveis de expressão de Fator de Crescimento Tumoral-&#946;1 (TGF-&#946;1), Colágeno Tipo I (Col-I) e Colágeno Tipo III (Col-III) estavam maiores no grupo TC em comparação com o grupo de controle. A análise ultraestrutural revelou a presença de feixes de colágeno no grupo tratado, e mostrou que a arquitetura do tecido do ovário estava mais desorganizada neste grupo comparado ao grupo controle. Os resultados obtidos neste trabalho indicam que a combinação de ciclofosfamida e docetaxel, um recente regime quimioterápico proposto para o tratamento do CM, pode levar a importantes alterações no ovário. O processo inflamatório, desencadeado pela administração dos quimioterápicos, estimula a apoptose e liberação de TGF-&#946; no estroma ovariano, que induz a produção de matriz extracelular e subsequente, substituição do tecido sadio por tecido fibrótico. A principal consequência deste processo é a diminuição, ou perda, da função ovariana, levando à menopausa precoce e possível infertilidade. É importante compreender os mecanismos envolvidos na infertilidade provocada pelo regime TC, a fim de estudar novos métodos que evitem este efeito indesejável em mulheres submetidas a tratamento do CM. / Breast cancer (BC) is the second most common cancer worldwide. It is known that the highest incidence of BC occurs in postmenopausal women, however an increasing number of young women have been affected by this disease. CM treatment may include: chemotherapy, radiotherapy and/or hormonotherapy. Chemotherapy is a systemic treatment that can cause significant side effects, including the ovarian failure induced by chemotherapy (CIOF). The main consequences of CIOF are infertility, and late complications related to the reduction of estrogen, such as osteoporosis and cardiovascular disease. The chemotherapy regimen TC, adopts the combination of docetaxel with cyclophosphamide as an option by drugs that result in rate of survival free cancer, and fewer side effects. This study aimed to determine the late effects in the ovary caused by the treatment with the combination of two chemotherapy agents: docetaxel and cyclophosphamide (TC), using an animal model with Wistar rats. To check the synergism of these chemotherapy agents and thus analyze the effect of co-administration, Wistar female rats were divided into two groups: a control group and a TC group. They were subjected to euthanasia five months after the end of treatment, and their plasma and ovaries were collected. Important alterations were noted. The plasma estradiol level was significantly reduced in the TC group compared with the control group. Additionally, the number of apoptotic nuclei was higher in the TC group. The role of the inflammatory response in the development of ovarian damage was investigated, and we found an increased number of mast cells and increased expression of Tumor necrosis fator-&#945; (TNF-&#945;) in the TC group. The involvement of fibrosis was also investigated. The results showed that the TC group had increased expression levels of Transforming growth factor-&#946;1 (TGF-&#946;1), Collagen Type I (col-I) and Collagen Type III (col-III) compared with the control group. Ultrastructural analysis revealed the presence of collagen bundles in the treated group and showed that the ovarian tissue architecture was more disorganized in this group than in the control group. The results of this study indicate that the combination of cyclophosphamide and docetaxel, a recent proposed chemotherapy regimen for the treatment of CM can lead to significant changes in the ovary. The inflammatory process, triggered by the administration of chemotherapy, stimulates apoptosis and release of TGF- &#946;1 in ovarian stroma, which induces extracellular matrix production, and subsequent, replacement of healthy tissue by fibrous tissue. The main consequence of this process is the reduction or loss of ovarian function, leading to early menopause and possible infertility. It is important to understand the mechanisms involved in the infertility provoked by the TC treatment, in order to study new methods which avoid this undesirable effect on women submitted to BC treatment.

<p>Chromosomal abnormalities are defined as changes in the chromosome structure and fall in one of two categories. The first category is numerical alterations while the second category consists of structural abnormalities. Structural chromosomal abnormalities do not always interrupt genes in order to cause disease. They can also affect gene expression by separating a gene and its promoter element from distant regulatory elements. We have used characterisation of structural chromosomal abnormalities to identify the genetic bases for several congenital disorders.</p><p>In papers I-III, we have applied molecular characterisation of chromosomal translocations in order to identify candidate genes involved in mental retardation, hypospadias and anal malformation and premature ovarian failure. In paper I, we localised the chromosome X translocation breakpoint in a t(X;15) to be in the immediate proximity of the gene <i>ZDHHC15 </i>in a patient with severe mental retardation. Subsequent experiments revealed loss of <i>ZDHHC15</i> transcription in the patient which suggests this gene to be involved in the aetiology of the patient’s phenotype. In paper II, we show that a balanced translocation between chromosomes 6 and 17 in a patient with urogential malformation disrupts 2 genes, one at each translocation breakpoint. We also identified a fusion-gene as a result of the translocation. Our hypethesis is that the translocation together with its molecular consequences is important for the phenotype in the patient. Similarly, in paper III, we have used molecular characterisation of the breakpoints in a balanced translocation between chromosomes X and 11 in order to localise candidate genes in ovarian function. Our results indicate a number of genes affected by the translocation. In paper IV, we have used array-based comparative genomic hybridisation (array-CGH) in order to investigate a cohort of autistic sib-pairs for submicroscopic chromosomal alterations. We have identified several novel duplications and one novel deletion with strong association with autism.</p>

Chromosomal abnormalities are defined as changes in the chromosome structure and fall in one of two categories. The first category is numerical alterations while the second category consists of structural abnormalities. Structural chromosomal abnormalities do not always interrupt genes in order to cause disease. They can also affect gene expression by separating a gene and its promoter element from distant regulatory elements. We have used characterisation of structural chromosomal abnormalities to identify the genetic bases for several congenital disorders. In papers I-III, we have applied molecular characterisation of chromosomal translocations in order to identify candidate genes involved in mental retardation, hypospadias and anal malformation and premature ovarian failure. In paper I, we localised the chromosome X translocation breakpoint in a t(X;15) to be in the immediate proximity of the gene ZDHHC15 in a patient with severe mental retardation. Subsequent experiments revealed loss of ZDHHC15 transcription in the patient which suggests this gene to be involved in the aetiology of the patient’s phenotype. In paper II, we show that a balanced translocation between chromosomes 6 and 17 in a patient with urogential malformation disrupts 2 genes, one at each translocation breakpoint. We also identified a fusion-gene as a result of the translocation. Our hypethesis is that the translocation together with its molecular consequences is important for the phenotype in the patient. Similarly, in paper III, we have used molecular characterisation of the breakpoints in a balanced translocation between chromosomes X and 11 in order to localise candidate genes in ovarian function. Our results indicate a number of genes affected by the translocation. In paper IV, we have used array-based comparative genomic hybridisation (array-CGH) in order to investigate a cohort of autistic sib-pairs for submicroscopic chromosomal alterations. We have identified several novel duplications and one novel deletion with strong association with autism.