Ovarian Folliculogenesis

卵巢卵泡发生

基本信息

批准号：
7734698
负责人：
Lawrence M Nelson
金额：
$ 108.92万
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
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/7734698
关键词：
5&apos Untranslated Regions Accounting Adrenal Glands Age Amenorrhea Androgens Antral Basic Science Caring Child Clinical Clinical Trials Collaborations Condition Confidence Intervals Controlled Study Daily Development Developmental Delay Disorders Diagnosis Disease Disruption Distress Drops Emotional Estradiol Estrogen Replacement Therapy Estrogen Therapy Estrogens Exons Family member Female Fertility Follow-Up Studies Fragile X Syndrome Functional disorder Gene Frequency Genes Genetic Genetic Polymorphism Genetic Variation Goals Health Hormones Human Infertility Inherited International Interview Investigation Irregular Menstruation Life Link Lower Limit of Normal Measures Medical Medroxyprogesterone 17-Acetate Menopause Menstruation Menstruation Disturbances Mental Retardation Methods Modeling Molecular Mus Mutation Neurologic Numbers Oral Ovarian Ovarian Follicle Ovary Ovulation Patient Self-Report Patients Personal Satisfaction Physiological Play Premature Menopause Premature Ovarian Failure Premenopause Primordial Follicle Process Production Protocols documentation Purpose Quality of life Questionnaires RNA Splicing Rate Recruitment Activity Replacement Therapy Reporting Reproduction Research Risk Role Sampling Score Self-Administered Serum Sex Functioning Sex Hormone-Binding Globulin Sexual Dysfunction Single Nucleotide Polymorphism Site-Directed Mutagenesis Social support Source Spirituality Standards of Weights and Measures Statistically Significant Structure Symptoms Testing Testosterone Time Treatment Protocols Trinucleotide Repeats Turner&apos s Syndrome Variant Woman Women&apos s Group Xp11.2 Xq22 Xq26 coping day design emotional distress experience folliculogenesis forkhead protein improved insight instrument mouse model prospective psychologic reproductive response self esteem senescence

项目摘要

Genetic studies have identified several loci at Xq22, Xq26-28, and Xp11.2-p22.1 whose disruption has been associated with the development of spontaneous POI. Fragile X syndrome, an X-linked disorder, is the most common hereditary cause of mental retardation and developmental delay. In nearly all cases the disorder is caused by an expansion of CGG trinucleotide repeats in the 5 untranslated region of FMR1 (Fragile Site Mental Retardation 1 Gene). Interestingly, premutations in the FMR1 gene, located at Xq27.3, have been associated with the development of spontaneous 46,XX POI. We previously reported a case of a young woman with established spontaneous POI who conceived subsequent to the diagnosis and had a child who manifests mental retardation due to fragile X syndrome. The case illustrates the need to inform patients with POI regarding their increased risk of carrying a premutation in FMR1, their options for testing, and the potential implications for family members with regard to diagnosis of menstrual irregularity, developmental delay, and neurological symptoms. The forkhead transcription factor Foxo3 is a master regulator and potent suppressor of primordial follicle activation. Loss of Foxo3 function in the mouse leads to primary ovarian insufficiency due to global follicle activation. The mouse Foxo3 locus is haploinsufficient and Foxo3-/+ females undergo early reproductive senescence consistent with an increased rate of primordial follicle utilization. As part of an international collaboration we sought to determine if heterozygous or homozygous polymorphisms or mutations of the human orthologue FOXO3 contribute to primary ovarian insufficiency. The exons and flanking splice sequences of the gene were sequenced in a large number of women with idiopathic primary ovarian insufficiency (n = 302). A total of eight single-nucleotide polymorphisms (SNPs) were identified, revealing a substantial amount of genetic variation at this locus. Allelic frequencies in control samples excluded several of these variants as causal. For the remaining variants, site-directed mutagenesis was performed to assess their functional impact. However, these rare sequence variants were not associated with significant decreases in FOXO3 activity. Taken together, the findings suggest that, despite the potential for FOXO3 haploinsufficiency to cause primary ovarian insufficiency, FOXO3 mutations are not a common cause of primary ovarian insufficiency. We have been investigating womens psychological response to the diagnosis of spontaneous POI. We previously demonstrated that over two-thirds of women with POI were unsatisfied with the manner in which they were informed of the diagnosis. Nearly 90% reported that they experienced moderate to severe emotional distress at the time, the degree of which was positively correlated with the degree of dissatisfaction with the manner in which they had been informed of the diagnosis. They perceived that thorough and accurate medical information on POI, support of others, and spirituality were helpful in coping. The findings suggest that the manner in which patients are informed of this diagnosis can significantly impact their level of distress. Patients perceive a need for clinicians to spend more time with them and provide more information about primary ovarian insufficiency. Ninety percent of women with spontaneous POI reported to us in structured interviews that spirituality plays an important role in helping them cope with the emotional sequelae of this diagnosis. In a follow-up study, we demonstrated a statistically significant positive correlation between functional well-being and spiritual well-being by employing an instrument specifically designed and validated to measure spirituality apart from religiosity. Our findings suggest a need for a controlled interventional clinical trial to test the hypothesis that strategies to assist women in finding meaning and purpose in the diagnosis of spontaneous POI would improve their functional well-being and quality of life. A group of women with the disorder who receive standard management would serve as controls. We also tested the hypothesis that women with spontaneous primary ovarian insufficiency differ from control women with regard to perceived social support and investigated the relationship between perceived social support and self-esteem. We found that women with primary ovarian insufficiency had significantly lower scores than controls on the perceived social support scale and the self-esteem scale. Patients had a significant positive correlation between self-esteem scores and perceived social support. This supports the need for prospective controlled studies. Strategies to improve social support and self-esteem might provide an approach to reduce the emotional suffering that accompanies the life-altering diagnosis of spontaneous primary ovarian insufficiency. We are also investigating methods that might improve fertility in women with POI. In POI the normal process of ovulation usually fails to occur despite the presence of antral follicles in up to 78% of women with this disorder. We demonstrated previously that many of these follicles fail to function normally because they become lutienized prematurely due to the associated chronically elevated serum LH levels. Theoretically estrogen replacement therapy might improve ovulation rates in women with spontaneous POI by reducing the associated chronically elevated serum LH levels to normal. We found that a regimen of 100 microgram per day of transdermal estradiol replacement achieves normal serum LH levels in approximately one-half of women with spontaneous POI. Theoretically, physiologic estradiol replacement therapy might improve follicle function in these women. We are planning controlled studies to assess the effect of estradiol replacement on ovulation in these women. The normal premenopausal ovary is an important source of androgen as well as estrogen production. In premenopausal women the daily testosterone production is approximately 300 micrograms, of which approximately half is derived from the ovaries and half from the adrenal glands. While off estrogen therapy, we found that patients with POI had median serum free testosterone concentrations that were significantly lower than those in controls. While on physiologic transdermal estradiol therapy, their median serum free testosterone dropped significantly lower even though their sex hormone binding globulin levels did not change. While on estradiol replacement 13% of women (95% confidence interval 7.9-20.3%) had serum free testosterone levels below the lower limit of normal. No controlled studies to date have specifically evaluated sexual function in women who have spontaneous 46,XX POI. We sought to determine if women with this condition who have been given estradiol replacement have sexual dysfunction as compared to young women of similar age who have normal ovarian function. Sexual dysfunction can have harmful effects on relationships, self-esteem, and quality of life. We assessed sexual function in women with spontaneous 46,XX POI (N=143) after at least 3 months of a standardized hormone replacement regimen (100 micrograms/day estradiol patch, oral medroxyprogesterone acetate 10 mg for 12 days each month). We compared our findings to control women (N=70) who had normal ovarian function and regular menstrual periods. We employed the Derogatis Interview for Sexual Function Self Report (DISF-SR), a validated self-administered questionnaire. Women with POI had significantly lower DISF-SR composite scores as compared to control women. Their serum total testosterone levels were significantly correlated with DISF-SR composite score, although this accounted for only 4% of the variance in this measure.

遗传研究已经在XQ22，XQ26-28和XP11.2-P22.1上确定了几个基因座，其破坏与自发POI的发展有关。 X连锁疾病脆弱的X综合征是最常见的遗传性智力低下和发育延迟的原因。在几乎所有情况下，该疾病都是由于FMR1的5个未翻译区域（脆弱的位点智力低下1基因）的CGG三核苷酸重复序列的扩展引起的。有趣的是，位于XQ27.3的FMR1基因中的预言与自发46，XX POI的发展有关。我们以前报道了一个年轻女子患有自发性POI的年轻女子，她在诊断后构思，并有一个孩子表现出由于脆弱的X综合征而表现出精神障碍。该案例表明，有必要将POI患者告知其在fMR1中携带预先享受的风险，测试的选择以及对家庭成员的潜在影响，以诊断月经不规则性，发育迟缓和神经系统症状。叉头转录因子FOXO3是主要调节剂，并且是原始卵泡激活的有效抑制剂。小鼠中FOXO3功能的丧失导致由于全球卵泡激活而导致的原发性卵巢不足。小鼠FOXO3基因座不足，FOXO3 - /+雌性经历了早期生殖衰老，这与原始卵泡利用率的增加一致。作为国际合作的一部分，我们试图确定人类直系同源物FOXO3的杂合或纯合多态性或纯合多态性或突变是否有助于原发性卵巢不足。在许多特发性原发性卵巢不足的女性中对基因的外显子和侧翼剪接序列进行了测序（n = 302）。总共确定了八个单核苷酸多态性（SNP），揭示了该基因座的大量遗传变异。对照样品中的等位基因频率将其中几种变体排除为因果关系。对于其余的变体，进行了定向的诱变以评估其功能影响。但是，这些罕见的序列变体与FOXO3活性的显着降低无关。综上所述，发现的结果表明，尽管FOXO3单倍不足会导致原发性卵巢不足，但FOXO3突变并不是原发性卵巢不足的常见原因。我们一直在调查女性对自发POI诊断的心理反应。我们以前证明，超过三分之二的POI女性对他们的诊断方式不满意。近90％的人报告说，他们当时遭受了中度至严重的情绪困扰，其程度与对诊断的方式的不满程度正相关。他们认为有关POI，其他人的支持和灵性的详尽准确的医学信息有助于应对。研究结果表明，告知患者这种诊断的方式可能会严重影响他们的困扰水平。患者认为临床医生需要花更多的时间与他们在一起，并提供有关原发性卵巢不足的更多信息。有90％的自发POI女性在结构化的访谈中向我们报告了灵性在帮助她应对这种诊断的情感后遗症方面起着重要作用。在一项后续研究中，我们通过采用专门设计和验证的工具来衡量精神性，而不是宗教信仰，我们证明了功能福祉和精神福祉之间具有统计学意义的正相关。我们的发现表明，需要进行对照介入的临床试验，以检验以下假设：帮助妇女找到自发POI诊断的意义和目的的策略将改善其功能福祉和生活质量。一群患有标准管理的疾病的妇女将用作控制。我们还检验了以下假设：自发性卵巢卵巢妇女在感知的社会支持方面与控制妇女有所不同，并研究了感知到的社会支持与自尊之间的关系。我们发现，原发性卵巢不足的妇女的得分明显低于感知到的社会支持量表和自尊量表上的对照。自尊得分和感知的社会支持之间的患者有显着的正相关。这支持对前瞻性对照研究的需求。改善社会支持和自尊的策略可能会提供一种方法来减少自发性原发性卵巢不足诊断的情感痛苦。我们还正在调查可能改善POI女性生育能力的方法。在POI中，尽管多达78％的患有这种疾病的女性中存在肛门卵泡，但通常不会发生排卵的正常过程。我们以前证明，这些卵泡中的许多都无法正常发挥作用，因为它们由于相关的长血清LH水平而过早地变成了浅色。从理论上讲，雌激素替代疗法可以通过将相关的长血清LH水平降低到正常水平，从而提高自发性POI女性的排卵率。我们发现，每天100微克雌二醇替代的方案可在大约一半的自发POI女性中达到正常的血清LH水平。从理论上讲，生理雌二醇替代疗法可能会改善这些女性的卵泡功能。我们正在计划对照研究，以评估雌二醇替代对这些女性排卵的影响。正常的绝经前卵巢是雄激素和雌激素产生的重要来源。在绝经前女性中，每日睾丸激素的产生约为300微克，其中大约一半来自卵巢，一半来自肾上腺。在雌激素疗法范围内，我们发现POI患者的中位血清无睾丸激素浓度明显低于对照组的睾丸激素浓度。在生理透皮雌二醇疗法上，即使他们的性激素结合球蛋白水平没有变化，它们的中位血清睾丸激素也明显降低。而在雌二醇替代品上，有13％的女性（95％置信区间7.9-20.3％）的血清无睾丸激素水平低于正常下限。迄今为止，尚无对照研究专门评估了自发的46岁POI的女性的性功能。我们试图确定与具有正常卵巢功能的年龄相似的年轻女性相比，接受雌二醇替代的妇女是否具有性功能障碍。性功能障碍会对人际关系，自尊和生活质量产生有害影响。我们在至少3个月的标准化激素替代方案（100微克/天雌二醇斑块，口服甲状腺甲酸酯10 mg的100微克/天雌二醇斑块中，每月12天）评估了至少3个月后3个月的自发性46，XX POI（n = 143）的性功能。我们将我们的发现与控制卵巢功能正常和常规月经期的女性（n = 70）进行了比较。我们采用了derogatis访谈进行性功能自我报告（DISF-SR），这是经过验证的自我管理问卷。与对照女性相比，患有POI的女性DISF-SR综合评分明显降低。他们的血清总睾丸激素水平与DISF-SR复合评分显着相关，尽管这仅占此量度方差的4％。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Screening for known mutations in EIF2B genes in a large panel of patients with premature ovarian failure.

DOI：
10.1186/1472-6874-4-8
发表时间：
2004-10-26
期刊：
BMC women's health
影响因子：
0
作者：
Fogli A;Gauthier-Barichard F;Schiffmann R;Vanderhoof VH;Bakalov VK;Nelson LM;Boespflug-Tanguy O
通讯作者：
Boespflug-Tanguy O

Investigation of KIT gene mutations in women with 46,XX spontaneous premature ovarian failure.