Ovarian Folliculogenesis

卵巢卵泡发生

• 批准号: 7594141
• 负责人: Lawrence M Nelson
• 金额: $ 266.1万
• 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/7594141
• 关键词: 3p24; 5' Untranslated Regions; Affect; Age; Amenorrhea; Amino Acids; Androgens; Animal Model; BMP15 gene; Basic Science; Candidate Disease Gene; Caring; Case Study; Characteristics; Child; Clinical; Clinical Trials; Code; Collaborations; Condition; Controlled Study; Development; Developmental Delay Disorders; Diagnosis; Dialysis procedure; Disease; Disruption; Distress; Emotional; Equilibrium; Estradiol; Estrogen Replacement Therapy; Estrogen Replacements; Estrogens; Exhibits; Exons; Family member; Female; Fertility; Follow-Up Studies; Fragile X Syndrome; Functional disorder; Gametogenesis; Gene Family; Genes; Genetic; Genetic Variation; Goals; Growth; Health; Hematopoiesis; Hormones; Human; Individual; Infertility; Inherited; International; Interview; Investigation; Irregular Menstruation; KIT gene; KITLG gene; Light; Link; Literature; Lower Limit of Normal; Luteinization; Measurable; Measures; Medical; Melanogenesis; Menopause; Menstruation Disturbances; Mental Retardation; Methods; Missense Mutation; Modeling; Molecular; Mus; Mutation; Neurologic; Normal Range; Ovarian; Ovarian Follicle; Ovary; Patients; Personal Satisfaction; Phenotype; Physical Dialysis; Physiological; Pigmentation physiologic function; Play; Point Mutation; Positioning Attribute; Premature Menopause; Premature Ovarian Failure; Premenopause; Production; Proto-Oncogene Protein c-kit; Protocols documentation; Psychosocial Factor; Purpose; Quality of life; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Relative (related person); Replacement Therapy; Reporting; Reproduction; Research; Risk; Role; Sampling; Score; Series; Serum; Sex Functioning; Single Nucleotide Polymorphism; Source; Spirituality; Staging; Standards of Weights and Measures; Statistically Significant; Steel; Stem Cell Factor; Structure; Structure of primordial sex cell; Symptoms; Testing; Testosterone; Time; Transforming Growth Factor beta; Treatment Protocols; Trinucleotide Repeats; Turner' s Syndrome; Variant; Woman; Women' s Group; Xp11.2; Xq22; Xq26; base; bone morphogenic protein; concept; coping; day; design; folliculogenesis; genetic analysis; improved; insight; instrument; member; mouse model; primary amenorrhea; proliferative phase Menstrual cycle; protein function; psychologic; psychological distress; reproductive; research study; response; self esteem

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 primary ovarian insufficiency (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 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. Members of the TGF beta superfamily play a role in supporting normal ovarian function. One member of this family, the gene for bone morphogenic protein 15 (BMP 15), is located at Xp11.2. Based on evidence in animal models, as well as a case report linking an A to G transition at position 704 of the BMP15 gene with familial POI, we participated in an international collaboration to perform BMP15 genetic analysis in a large series of women with spontaneous POI. We found heterozygous gene BMP15 gene variants in 7 of 166 patients, significantly more than in controls. Given that BMP15 is within the Xp locus linked to POI, the findings support the concept that BMP15 represents one of the genes whose haploinsufficiency significantly contributes to the POI in Turner syndrome. Deleted in AZoospermia-Like (DAZL), located at 3p24, is another candidate gene for POI. Rather than focusing on rare amino acid changes that severely impair protein function, this effort primarily tested the hypothesis that common variants, or SNPs (single nucleotide polymorphisms) might in aggregate have a measurable effect on the development of POI. We found that SNPs in the DAZL gene may act singly or jointly to affect reproductive characteristics of women. In addition, sequencing of the entire coding region of DAZL, including all exons and flanking regions, identified four putative missense mutations. Further studies may shed light on the role of DAZL in the development of spontaneous POI. Foxo3-null female mice exhibit a distinctive ovarian phenotype of global follicle activation leading to early depletion of functional follicles. Foxo3 functions at the earliest stages of follicle growth as a suppressor of follicle activation. We participated in an international collaboration to test the hypothesis that sequence variation at the human FOXO3 locus is a mechanism of POI and primary amenorrhea. Taken together, our findings do not exclude the possibility that FOXO3 mutations contribute to POI or primary amenorrhea in some individuals, but argue that de novo FOXO3 mutations are not a common cause of either condition. Mice with mutations in the c-kit tyrosine kinase receptor Kit (W) and the c-kit ligand Kitlg (Steel) have impaired development of primordial germ cells. Both KIT and KITLG play critical roles in gametogenesis, as well as hematopoiesis and melanogenesis. Point mutations in the mouse Kit receptor tyrosine kinase can selectively impair fertility without inducing detectable abnormalities in hematopoiesis or pigmentation. However, in previous experiments, we found that mutation of the KIT gene appears not to be a common cause of 46,XX spontaneous POI in women. We recently demonstrated that mutations in the coding regions of the KITLG gene also appear not to be a common cause of this condition. The normal premenopausal ovary is an important source of androgen as well as estrogen production. We thus undertook a study using the rigorous method of equilibrium dialysis to measure levels of circulating free testosterone in women with 46,XX spontaneous POI. We evaluated 130 such women while they were off any estrogen replacement therapy and then again 3 months later while receiving a standardized estradiol regimen. We sampled regularly menstruating control women during the mid follicular phase. While on estradiol replacement 13% of women had serum free testosterone levels below the lower limit of normal. The clinical implications of this testosterone deficiency may be significant, and we are currently investigating them further. No controlled studies to date have specifically evaluated sexual function in women who have spontaneous 46,XX POI. We assessed sexual function in women with spontaneous 46,XX POI (N=143) after at least 3 months of a standardized hormone replacement regimen. We compared our findings to control women (N=70). Sexual function is in the normal range for most young women with 46,XX spontaneous POI who are receiving physiologic estradiol replacement. As a group, however, these young women score significantly lower on a sexual function scale than control women. We are currently investigating the relative contributions of psychosocial factors and testosterone deficiency on the sexual function of these patients. We have been investigating womens psychological response to the diagnosis of spontaneous POI. In general, given that the inability to reproduce creates a profound loss for most women and affects their self-esteem and relationships with others, the literature has thoroughly documented the psychological distress of women with infertility. We previously demonstrated that over two-thirds of women with POI were unsatisfied with the manner in which they were 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 are also investigating methods to improve fertility in women with POI. We demonstrated previously that many of these follicles fail to function normally because they become lutienized prematurely due to chronically elevated serum LH levels. 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, by avoiding inappropriate luteinization, physiologic estradiol replacement therapy might improve follicle function in these women. We are undertaking controlled studies to assess the effect of estrogen replacement on follicle function in these women.

遗传研究已经在XQ22，XQ26-28和XP11.2-P22.1上确定了几个基因座，其破坏与自发性原发性卵巢不足（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。 我们报道了一个案例，一个年轻女子患有自发性POI，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。 TGF Beta超家族的成员在支持正常卵巢功能方面发挥了作用。 该家族的一个成员是骨形态蛋白15（BMP 15）的基因，位于XP11.2。 基于动物模型的证据以及与家族性POI的第704个位置上的A至G转变有关的案例报告，我们参加了国际合作，在许多自发POI的女性中进行了BMP15遗传分析。 我们发现杂合基因BMP15基因在166名患者中有7种，比对照组中明显多。 鉴于BMP15位于与POI相关的XP基因座之内，因此发现BMP15代表了其单倍弥补的基因之一，其单倍氨基调对Turner综合征的POI显着贡献。 位于3p24的Azoospermia样（DAZL）中删除，是POI的另一个候选基因。 这种努力并没有专注于严重损害蛋白质功能的稀有氨基酸变化，而是主要检验了一个假说，即在骨料中，常见变体或SNP（单核苷酸多态性）可能对POI的发展具有可测量的影响。 我们发现，DAZL基因中的SNP可能会单独或共同起作用以影响女性的生殖特征。 此外，包括所有外显子和侧翼区域在内的DAZL整个编码区域的测序确定了四个假定的错义突变。 进一步的研究可能会阐明DAZL在自发POI发展中的作用。 FOXO3无效的雌性小鼠表现出全球卵泡激活的独特卵巢表型，导致功能性卵泡的早期消耗。 FOXO3在卵泡生长的最早阶段起作用，作为卵泡激活的抑制剂。 我们参加了国际合作，以检验以下假设：人类FOXO3基因座的序列变化是POI和原发性闭经的机制。 综上所述，我们的发现并不排除某些个体中FOXO3突变有助于POI或原发性闭经的可能性，但认为Novo Foxo3突变并不是任何两种情况的常见原因。 C-KIT酪氨酸激酶受体试剂盒（W）和C-KIT配体KITLG（钢）中具有突变的小鼠受到原始生殖细胞的发育受损。 Kit和Kitlg在配子发生以及造血和黑色素发生中都起着关键作用。 小鼠试剂盒受体酪氨酸激酶中的点突变可以有选择地损害生育能力，而无需诱导造血或色素沉着的可检测异常。 但是，在先前的实验中，我们发现套件基因的突变似乎不是女性46，XX自发POI的常见原因。 我们最近证明，KITLG基因的编码区域中的突变似乎也不是这种情况的常见原因。 正常的绝经前卵巢是雄激素和雌激素产生的重要来源。 因此，我们使用严格的平衡透析方法进行了一项研究，以测量46个自发POI的女性中循环的游离睾丸激素水平。 我们在接受任何雌激素替代疗法的情况下评估了130个这样的女性，然后在3个月后再次接受标准化的雌二醇方案。 我们在卵泡期间定期对对照女性进行了定期月经。 而在雌二醇替代上，有13％的女性的血清睾丸激素水平低于正常的下限。 这种睾丸激素缺乏的临床意义可能很大，我们目前正在进一步研究它们。 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。 我们评估了至少3个月的标准激素替代方案3个月后，自发46，XX POI（n = 143）的性功能。 我们将我们的发现与对照女性进行了比较（n = 70）。 对于大多数接受生理雌二醇替代的46名自发性POI的年轻女性，性功能在正常范围内。 然而，作为一个小组，这些年轻女性在性功能量表上得分明显低于对照女性。 我们目前正在研究社会心理因素和睾丸激素缺乏对这些患者性功能的相对贡献。 我们一直在调查女性对自发POI诊断的心理反应。 总的来说，鉴于无法再现会给大多数女性带来深远的损失，并影响她们的自尊和与他人的关系，文献已经彻底证明了不孕症妇女的心理困扰。 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。 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。 我们还正在研究改善POI女性生育能力的方法。 我们以前证明，这些卵泡中的许多无法正常发挥作用，因为它们由于长期升高的血清LH水平过高而过早地变成了浅色。 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，通过避免不适当的黄体化，生理雌二醇替代疗法可以改善这些女性的卵泡功能。 我们正在进行对照研究，以评估雌激素替代对这些女性卵泡功能的影响。