卵巢早衰的遗传学病因分析和PTEN抑制剂对卵巢的作用及其安全性研究
|
摘要
卵巢是女性独特又重要的器官,主要功能是分泌性腺激素和产生健康成熟的卵子。卵巢功能恶化是一个逐渐进展的过程,临床上根据基础血清卵泡刺激素(Follicle-stimulating hormone, FSH)水平将女性分为卵巢功能正常(<10lU/L)、卵巢功能低下(≥10IU/L且≤40IU/L)和卵巢早衰(Premature ovarian failure, POF)(>40IU/L)。美国生殖医学学会因而提出了原发性卵巢功能不全(Primary ovarian insufficiency, POI)的概念,涵盖了卵巢功能低下和POF,体现了疾病的进展性和多样性。
POF是卵巢功能恶化的终末阶段,是指女性40岁前因性腺功能衰竭出现原发性或继发性闭经,伴有促性腺激素水平升高、雌激素水平降低等内分泌异常和生殖器官萎缩等围绝经期表现。目前己发现的POF发病机制包括染色体结构或数目异常、基因突变、自身免疫性疾病和医源性因素等,但多数病因不清者属于“特发性卵巢早衰”。第一章分别通过POF患者的染色体核型分析、PTEN基因序列研究、SKP2-P27信号通路研究和全基因组关联分析4个方面探讨了POF的遗传学病因。结果显示,X染色体尤其是Xq13-27是POF患者最常见的染色体核型异常位点；首次发现PTEN基因不是中国汉族POF患者的常见病因；首次发现SKP2-P27信号通路不是中国汉族POF患者的常见病因和首次发现POF的遗传易感新区域8q22.3。这些研究结果为进一步研究POF的病因和临床治疗对策提供了线索和帮助。
基础研究是为了更好的服务于临床,因此我们积极开展以POF和卵巢功能低下患者的临床对策为导向的理论研究。当女性具备POF的易感性,如存在某个己知POF相关基因的突变等遗传因素,应鼓励其尽早生育。对于暂无生育计划的女性,卵巢组织冷冻不失为一个理想的选择。卵巢组织中绝大部分卵泡是原始卵泡,而这些原始卵泡尚未激活和发育成熟,不能直接用于体外受精。另外,目前POF在临床上尚无有效的治疗手段,而研究显示卵巢功能低下甚至POF患者的卵巢内仍存在数量不等的原始卵泡。因此如何利用原始卵泡使其激活进一步发育至可受精的成熟卵泡成为一个亟需解决的难题。最近研究发现PTEN抑制剂培养小鼠和人类卵巢组织能促进原始卵泡激活,并使之发育到成熟卵泡。但PTEN抑制剂应用的安全性尚未得到评估。第二章利用小鼠模型进一步研究了PTEN抑制剂对于激活小鼠卵巢内原始卵泡的作用及其作用的安全性,以期为临床上POF的预防和不孕治疗提供理论基础。研究结果显示,PTEN抑制剂可以作为一种安全有效的技术,促进卵巢内原始卵泡激活并使之进一步发育至健康成熟卵泡。
相比POF,卵巢功能低下患者在临床上更常见,且很多进展为POF。卵巢功能低下这一阶段可能是部分患者进展到POF前实现生育的最后机会,她们的治疗同样值得关注。卵巢功能低下患者在辅助生殖治疗中用药剂量大、花费高、效果差,如何提前预测其卵巢反应和妊娠结局具有十分重要的意义。第三章研究了基础血清睾酮水平对卵巢功能低下患者在辅助生殖治疗中的预测价值。分析结果显示,基础血清睾酮水平能预测卵巢功能低下患者对促排卵药物的卵巢潜在低反应和妊娠结局,为临床上卵巢功能低下患者提前制定更合理的辅助生殖治疗方案和早期预防POF提供参考。
Chapter Ⅰ. Genetic Study of Premature Ovarian Failure Section Ⅰ. Karyotype Analysis of281Chinese Han Women with Premature Ovarian Failure
OBJECTIVE:The purpose of the present study is to analyze the chromosome karyotypes of premature ovarian failure (POF) in Chinese Han women and to study the association between abnormal type and site of chromosome with pathogenesis of POF.
METHODS:Peripheral blood was taken from281Chinese Han POF patients for lymphocytes cultivation and karyotype analysis was performed by G-banding technique. A minimum of30cells per patient were analyzed. Informed written consents were obtained from all participants.
RESULTS:(DAmong the281Chinese Han POF patients, there were235cases with normal chromosomal karyotype (83.6%,235/281); And46patients were identified with abnormal chromosomal karyotype (16.4%,46/281).(2)Among the abnormal karyotypes, there were34cases involved with X chromosome only,6subjects with autosomes only,4patients with chromosome translocation between X chromosome and autosome,1with46, XY and1with45, X/46,XY. X chromosome is the most common involved.(3)There were19cases with breakage, rearrangement or deletion in X chromosome, especially in Xq13-27.(4)The incidence of abnormal chromosome karyotype in POF patients with primary amenorrhea is26.3%(15/57), significantly higher than that in POF subjects with secondary amenorrhea (13.8%,31/224).
CONCLUSIONS:(1) Chromosomal abnormality is one of the most important etiologies of POF.(2)X chromosome is the most common involved in the abnormal chromosome karyotype, especially in Xq13-27.(3)It is very necessary to take chromosome karyotype examination in patients with POF especially patients with primary amenorrhea.
Section II. Mutational Analysis of PTEN in Chinese Women with Premature Ovarian Failure
OBJECTIVE:PTEN (phosphatase and tensin homolog deleted on chromosome10), originally identified as a tumor suppressor gene, has been recently demonstrated to play a role in the activation of primordial follicles. Lack of expression of the Pten gene in murine oocytes leads to premature ovarian failure (POF) due to accelerated depletion of the follicular pool. Mutational analysis of the PTEN gene in Chinese POF patients has not been done. The purpose of the present study is to investigate whether mutations in the PTEN gene may contribute to the etiology of Chinese idiopathic POF.
METHODS:We recruited161Chinese women with secondary amenorrhea associated with POF based on the phenotype of Pten knock-out mice and sequenced the PTEN gene on an automated sequencer.
RESULTS:Three known single-nucleotide polymorphisms (SNPs) were identified (rs11202592in the5' UTR region, rs34051577in intron4, and rs17849090in exon7). No plausible pathogenic mutations were detected. No additional SNPs or mutations were found in exons of the PTEN gene.
CONCLUSIONS:Our findings suggest that the PTEN gene may not be a common cause of Chinese women with POF. Future studies in large cohorts from different ethnic populations are warranted.
Section Ⅲ. Mutational analysis of SKP2and P27in Chinese Han women with premature ovarian failure
OBJECTIVE:P27and SKP2, a major regulator of P27, play a crucial role in ovarian function in mice. Both p27-deficient and.Skp2-deficient female mice developed premature ovarian failure (POF). Mutational analysis of the SKP2gene in POF patients has not been done. The purpose of the present study is to investigate whether mutations in the SKP2and P27gene may contribute to the etiology of Chinese idiopathic POF.
METHODS:We recruited200Chinese Han POF women and sequenced both the SKP2and P27gene on an automated sequencer. The coding region of SKP2and P27were examined in200Chinese women with POF, compared with200control volunteers.
RESULTS:One known single nucleotide polymorphism (SNP), rs61755301(c.846A>G) in exon7of SKP2and one known SNP (rs16908375, c.165G>A) in exon1of P27were identified respectively. Comparisons of genotype and allelic frequencies between POF cases and the general population showed no significant differences of the two SNPs. No additional SNPs or mutations were found.
CONCLUSIONS:The present study is the first to discover variants occurring in SKP2in association with POF. The results suggested that mutations in SKP2and P27are not common in Chinese Han women with POF.
Section Ⅳ. Genome-wide Association Study of Chinese Premature Ovarian Failure
OBJECTIVE:Premature ovarian failure (POF) is a complex heritable disorder known to be caused by chromosomal abnormalities and to date a limited number of known mutations. We sought to identify additional genetic loci associated with POF by performing the first large-scale genome-wide association study (GWAS).
METHODS:GWAS, using Affymetrix SNP6.0chip, was conducted in an initial discovery set of391well-documented Chinese Han POF patients, compared with895unrelated Chinese female controls. A replication study on the most significant loci was then performed in an independent set of400cases and800controls.
RESULTS:This GWAS, involving by far the largest sample of POF cases accumulated to date, revealed heretofore unrecognized association between POF and a novel genetic locus or region of unknown nature on8q22.3. Replication of eight single-nucleotide polymorphisms (SNPs)(rs10464815, rs10808365, rs3847152, rs3847153, rs3847154, rs3843552,rs10955242, rs3843555)(P≤3.86x10-6) was confirmed in verification sets. No specific candidate gene was found in the immediate region of8q22.3.
CONCLUSIONS:Suggestive significant associations were observed at8q22.3. We speculate existence of a long-distance regulatory region that has relevance to the control of ovarian differentiation or oogenesis.
Chapter Ⅱ. Safety Study of PTEN Inhibitor on Activation of Primordial Follicles
OBJECTIVE:Primordial ovarian follicles, which are often present in the ovaries of premature ovarian failure (POF) patients or are cryopreserved from the ovaries of young cancer patients who are undergoing gonadotoxic anticancer therapies, cannot be used to generate mature oocytes for in vitro fertilization (IVF). There has been very little success in triggering growth of primordial follicles to obtain fertilizable oocytes due to the poor understanding of the biology of primordial follicle activation. It was recently reported that PTEN (Phosphatase and tensin homolog deleted on chromosome10) prevents primordial follicle activation in mice, and deletion of Pten from the oocytes of primordial follicles leads to follicular activation. Consequently, the PTEN inhibitor has been successfully used in vitro to activate primordial follicles in both mouse and human ovaries. These results suggest that PTEN inhibitors could be used in ovarian culture medium to trigger the activation of primordial follicle. The purpose of the present study is to study the efficacy and safety of the use of PTEN inhibitor.
METHODS:Primordial follicles were activated from neonatal mouse ovaries by transient treatment with a PTEN inhibitor bpV(HOpic). These ovaries were then transplanted under the kidney capsules of recipient mice to generate mature oocytes. The mature oocytes were fertilized in vitro and progeny mice were obtained after embryo transfer.
RESULTS:Long-term monitoring up to the second generation of progeny mice showed that the mice were reproductively active and were free from any overt signs or symptoms of chronic illnesses.
CONCLUSIONS:Our results indicate that the use of PTEN inhibitors could be a safe and effective way of generating mature human oocytes for use in novel IVF techniques.
Chapter Ⅲ. PrognisticValue of Basal Serum Testosterone Levels in Women with Diminished Ovarian Reserve in Assisted Reproductive Technology
OBJECTIVE:To evaluate basal testosterone (T) levels during follicular phase of the menstrual cycle as a predictor in women with diminished ovarian reserve for ovarian response and in vitro fertilization (IVF) outcome.
METHODS:We analyzed data retrospectively from hospital-based IVF center including one hundred and eighty seven Chinese Han women with diminished ovarian reserve. We studied the association of basal T levels with ovarian response and IVF outcome.
RESULTS:Basal T levels were significantly different between pregnant and non-pregnant women. A testosterone level of47.85ng/dl was shown to predict pregnancy outcome with a sensitivity of52.8%and specificity of65.3%; and the basal T was correlated with the numbers of large follicles (>14mm) on HCG day. Significantly negative correlations were observed between basal T, days of stimulation and total dose of gonadotropins after adjusting for confounding factors.
CONCLUSIONS:In women with diminished ovarian reserve, lower level of basal T was associated with potential ovarian poor response. Basal T level could be used as a predictor for pregnancy outcome in IVF.
POF是卵巢功能恶化的终末阶段,是指女性40岁前因性腺功能衰竭出现原发性或继发性闭经,伴有促性腺激素水平升高、雌激素水平降低等内分泌异常和生殖器官萎缩等围绝经期表现。目前己发现的POF发病机制包括染色体结构或数目异常、基因突变、自身免疫性疾病和医源性因素等,但多数病因不清者属于“特发性卵巢早衰”。第一章分别通过POF患者的染色体核型分析、PTEN基因序列研究、SKP2-P27信号通路研究和全基因组关联分析4个方面探讨了POF的遗传学病因。结果显示,X染色体尤其是Xq13-27是POF患者最常见的染色体核型异常位点；首次发现PTEN基因不是中国汉族POF患者的常见病因；首次发现SKP2-P27信号通路不是中国汉族POF患者的常见病因和首次发现POF的遗传易感新区域8q22.3。这些研究结果为进一步研究POF的病因和临床治疗对策提供了线索和帮助。
基础研究是为了更好的服务于临床,因此我们积极开展以POF和卵巢功能低下患者的临床对策为导向的理论研究。当女性具备POF的易感性,如存在某个己知POF相关基因的突变等遗传因素,应鼓励其尽早生育。对于暂无生育计划的女性,卵巢组织冷冻不失为一个理想的选择。卵巢组织中绝大部分卵泡是原始卵泡,而这些原始卵泡尚未激活和发育成熟,不能直接用于体外受精。另外,目前POF在临床上尚无有效的治疗手段,而研究显示卵巢功能低下甚至POF患者的卵巢内仍存在数量不等的原始卵泡。因此如何利用原始卵泡使其激活进一步发育至可受精的成熟卵泡成为一个亟需解决的难题。最近研究发现PTEN抑制剂培养小鼠和人类卵巢组织能促进原始卵泡激活,并使之发育到成熟卵泡。但PTEN抑制剂应用的安全性尚未得到评估。第二章利用小鼠模型进一步研究了PTEN抑制剂对于激活小鼠卵巢内原始卵泡的作用及其作用的安全性,以期为临床上POF的预防和不孕治疗提供理论基础。研究结果显示,PTEN抑制剂可以作为一种安全有效的技术,促进卵巢内原始卵泡激活并使之进一步发育至健康成熟卵泡。
相比POF,卵巢功能低下患者在临床上更常见,且很多进展为POF。卵巢功能低下这一阶段可能是部分患者进展到POF前实现生育的最后机会,她们的治疗同样值得关注。卵巢功能低下患者在辅助生殖治疗中用药剂量大、花费高、效果差,如何提前预测其卵巢反应和妊娠结局具有十分重要的意义。第三章研究了基础血清睾酮水平对卵巢功能低下患者在辅助生殖治疗中的预测价值。分析结果显示,基础血清睾酮水平能预测卵巢功能低下患者对促排卵药物的卵巢潜在低反应和妊娠结局,为临床上卵巢功能低下患者提前制定更合理的辅助生殖治疗方案和早期预防POF提供参考。
Chapter Ⅰ. Genetic Study of Premature Ovarian Failure Section Ⅰ. Karyotype Analysis of281Chinese Han Women with Premature Ovarian Failure
OBJECTIVE:The purpose of the present study is to analyze the chromosome karyotypes of premature ovarian failure (POF) in Chinese Han women and to study the association between abnormal type and site of chromosome with pathogenesis of POF.
METHODS:Peripheral blood was taken from281Chinese Han POF patients for lymphocytes cultivation and karyotype analysis was performed by G-banding technique. A minimum of30cells per patient were analyzed. Informed written consents were obtained from all participants.
RESULTS:(DAmong the281Chinese Han POF patients, there were235cases with normal chromosomal karyotype (83.6%,235/281); And46patients were identified with abnormal chromosomal karyotype (16.4%,46/281).(2)Among the abnormal karyotypes, there were34cases involved with X chromosome only,6subjects with autosomes only,4patients with chromosome translocation between X chromosome and autosome,1with46, XY and1with45, X/46,XY. X chromosome is the most common involved.(3)There were19cases with breakage, rearrangement or deletion in X chromosome, especially in Xq13-27.(4)The incidence of abnormal chromosome karyotype in POF patients with primary amenorrhea is26.3%(15/57), significantly higher than that in POF subjects with secondary amenorrhea (13.8%,31/224).
CONCLUSIONS:(1) Chromosomal abnormality is one of the most important etiologies of POF.(2)X chromosome is the most common involved in the abnormal chromosome karyotype, especially in Xq13-27.(3)It is very necessary to take chromosome karyotype examination in patients with POF especially patients with primary amenorrhea.
Section II. Mutational Analysis of PTEN in Chinese Women with Premature Ovarian Failure
OBJECTIVE:PTEN (phosphatase and tensin homolog deleted on chromosome10), originally identified as a tumor suppressor gene, has been recently demonstrated to play a role in the activation of primordial follicles. Lack of expression of the Pten gene in murine oocytes leads to premature ovarian failure (POF) due to accelerated depletion of the follicular pool. Mutational analysis of the PTEN gene in Chinese POF patients has not been done. The purpose of the present study is to investigate whether mutations in the PTEN gene may contribute to the etiology of Chinese idiopathic POF.
METHODS:We recruited161Chinese women with secondary amenorrhea associated with POF based on the phenotype of Pten knock-out mice and sequenced the PTEN gene on an automated sequencer.
RESULTS:Three known single-nucleotide polymorphisms (SNPs) were identified (rs11202592in the5' UTR region, rs34051577in intron4, and rs17849090in exon7). No plausible pathogenic mutations were detected. No additional SNPs or mutations were found in exons of the PTEN gene.
CONCLUSIONS:Our findings suggest that the PTEN gene may not be a common cause of Chinese women with POF. Future studies in large cohorts from different ethnic populations are warranted.
Section Ⅲ. Mutational analysis of SKP2and P27in Chinese Han women with premature ovarian failure
OBJECTIVE:P27and SKP2, a major regulator of P27, play a crucial role in ovarian function in mice. Both p27-deficient and.Skp2-deficient female mice developed premature ovarian failure (POF). Mutational analysis of the SKP2gene in POF patients has not been done. The purpose of the present study is to investigate whether mutations in the SKP2and P27gene may contribute to the etiology of Chinese idiopathic POF.
METHODS:We recruited200Chinese Han POF women and sequenced both the SKP2and P27gene on an automated sequencer. The coding region of SKP2and P27were examined in200Chinese women with POF, compared with200control volunteers.
RESULTS:One known single nucleotide polymorphism (SNP), rs61755301(c.846A>G) in exon7of SKP2and one known SNP (rs16908375, c.165G>A) in exon1of P27were identified respectively. Comparisons of genotype and allelic frequencies between POF cases and the general population showed no significant differences of the two SNPs. No additional SNPs or mutations were found.
CONCLUSIONS:The present study is the first to discover variants occurring in SKP2in association with POF. The results suggested that mutations in SKP2and P27are not common in Chinese Han women with POF.
Section Ⅳ. Genome-wide Association Study of Chinese Premature Ovarian Failure
OBJECTIVE:Premature ovarian failure (POF) is a complex heritable disorder known to be caused by chromosomal abnormalities and to date a limited number of known mutations. We sought to identify additional genetic loci associated with POF by performing the first large-scale genome-wide association study (GWAS).
METHODS:GWAS, using Affymetrix SNP6.0chip, was conducted in an initial discovery set of391well-documented Chinese Han POF patients, compared with895unrelated Chinese female controls. A replication study on the most significant loci was then performed in an independent set of400cases and800controls.
RESULTS:This GWAS, involving by far the largest sample of POF cases accumulated to date, revealed heretofore unrecognized association between POF and a novel genetic locus or region of unknown nature on8q22.3. Replication of eight single-nucleotide polymorphisms (SNPs)(rs10464815, rs10808365, rs3847152, rs3847153, rs3847154, rs3843552,rs10955242, rs3843555)(P≤3.86x10-6) was confirmed in verification sets. No specific candidate gene was found in the immediate region of8q22.3.
CONCLUSIONS:Suggestive significant associations were observed at8q22.3. We speculate existence of a long-distance regulatory region that has relevance to the control of ovarian differentiation or oogenesis.
Chapter Ⅱ. Safety Study of PTEN Inhibitor on Activation of Primordial Follicles
OBJECTIVE:Primordial ovarian follicles, which are often present in the ovaries of premature ovarian failure (POF) patients or are cryopreserved from the ovaries of young cancer patients who are undergoing gonadotoxic anticancer therapies, cannot be used to generate mature oocytes for in vitro fertilization (IVF). There has been very little success in triggering growth of primordial follicles to obtain fertilizable oocytes due to the poor understanding of the biology of primordial follicle activation. It was recently reported that PTEN (Phosphatase and tensin homolog deleted on chromosome10) prevents primordial follicle activation in mice, and deletion of Pten from the oocytes of primordial follicles leads to follicular activation. Consequently, the PTEN inhibitor has been successfully used in vitro to activate primordial follicles in both mouse and human ovaries. These results suggest that PTEN inhibitors could be used in ovarian culture medium to trigger the activation of primordial follicle. The purpose of the present study is to study the efficacy and safety of the use of PTEN inhibitor.
METHODS:Primordial follicles were activated from neonatal mouse ovaries by transient treatment with a PTEN inhibitor bpV(HOpic). These ovaries were then transplanted under the kidney capsules of recipient mice to generate mature oocytes. The mature oocytes were fertilized in vitro and progeny mice were obtained after embryo transfer.
RESULTS:Long-term monitoring up to the second generation of progeny mice showed that the mice were reproductively active and were free from any overt signs or symptoms of chronic illnesses.
CONCLUSIONS:Our results indicate that the use of PTEN inhibitors could be a safe and effective way of generating mature human oocytes for use in novel IVF techniques.
Chapter Ⅲ. PrognisticValue of Basal Serum Testosterone Levels in Women with Diminished Ovarian Reserve in Assisted Reproductive Technology
OBJECTIVE:To evaluate basal testosterone (T) levels during follicular phase of the menstrual cycle as a predictor in women with diminished ovarian reserve for ovarian response and in vitro fertilization (IVF) outcome.
METHODS:We analyzed data retrospectively from hospital-based IVF center including one hundred and eighty seven Chinese Han women with diminished ovarian reserve. We studied the association of basal T levels with ovarian response and IVF outcome.
RESULTS:Basal T levels were significantly different between pregnant and non-pregnant women. A testosterone level of47.85ng/dl was shown to predict pregnancy outcome with a sensitivity of52.8%and specificity of65.3%; and the basal T was correlated with the numbers of large follicles (>14mm) on HCG day. Significantly negative correlations were observed between basal T, days of stimulation and total dose of gonadotropins after adjusting for confounding factors.
CONCLUSIONS:In women with diminished ovarian reserve, lower level of basal T was associated with potential ovarian poor response. Basal T level could be used as a predictor for pregnancy outcome in IVF.
引文
1. Luborsky JL, Meyer P, Sowers MF, Gold EB, Santoro N. Premature menopause in a multi-ethnic population study of the menopause transition. Hum Reprod. 2003;18:199-206.
2. Kalantaridou SN, Davis SR, Nelson LM. Premature ovarian failure.Endocrinol Metab Clin North Am.1998;27:989-1006.
3. Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update. 2005;11:391-410.
4. Christin-Maitre S, Pasquier M, Donadille B, Bouchard P. Premature ovarian failure. Ann Endocrinol (Paris).2006;67:557-66.
5. Portnoi MF, Aboura A, Tachdjian G, Bouchard P, Dewailly D, Bourcigaux N, Frydman R, Reyss AC, Brisset S, Christin-Maitre S. Molecular cytogenetic studies of Xq critical regions in premature ovarian failure patients. Hum Reprod. 2006; 21:2329-34.
6. Zinn AR. The X chromosome and the ovary. Soc Gynecol Investig. 2001;8:S34-6.
7. Devi A, Benn PA. X-Chromosome abnormalities in women with premature ovarian failure. J Reprod Med 1999; 44:321.
8. Bakalov VK, Axelrod L, Baron J, Hanton L, Nelson LM, Reynolds JC, Hill S, Troendle J, Bondy CA. Selective reduction in cortical bone mineral density in turner syndrome independent of ovarian hormone deficiency. J Clin Endocrinol Metab.2003;88:5717-22.
9. 李程.程茜Turner综合征临床表现的遗传学基础研究进展.中国实用儿科杂志,2007:546-548.
10. Yaron Y, Ochshorn Y, Amit A, Yovel I, Kogosowki A, Lessing JB. Patients with Turner's syndrome may have an inherent endometrial abnormality affecting receptivity in oocyte donation. Fertil Steril.1996; 65:1249-52.
11. Blair J, Tolmie J, Hollman AS, Donaldson MD. Phenotype, ovarian function, and growth in patients with 45, X/47, ⅩⅩⅩ Turner mosaicism:Implications for prenatal counseling and estrogen therapy at puberty. J Pediatr.2001;139:724-8.
12. Mazzanti L, Cicognani A, Baldazzi L, Bergamaschi R, Scarano E, Strocchi S, Nicoletti A, Mencarelli F, Pittalis M, Forabosco A, Cacciari E. Gonadoblastoma in Turner syndrome and Y-chromosome-derived material. Am J Med Genet A. 2005;135:150-4.
13. Hanson L, Bryman I, Janson PO, Jakobsen AM, Hanson C. Fluorescence in situ hybridization analysis and ovarian histology of women with Turner syndrome presenting with Y-chromosomal material:a correlation between oral epithelial cells, lymphocytes and ovarian tissue. Hereditas.2002;137:1-6.
14. Rooman RP, Van Driessche K, Du Caju MV. Growth and ovarian function in girls with 48, XXXX karyotype--patient report and review of the literature. J Pediatr Endocrinol Metab.2002; 15:1051-5.
15. Holland CM.47, XXX in an adolescent with premature ovarian failure and autoimmune disease. J Pediatr Adolesc Gynecol.2001; 14:77-80.
16. Holland CM.47, XXX in an adolescent with premature ovarian failure and autoimmune disease. J Pediatr Adolesc Gynecol. J Pediatr Adolesc Gynecol. 2000; 13:93..
17. Goswami R, Goswami D, Kabra M, Gupta N, Dubey S, Dadhwal V. Prevalence of the triple X syndrome in phenotypically normal women with premature ovarian failure and its association with autoimmune thyroid disorders. Fertil Steril.2003;80:1052-4.
18. Mazzanti L, Cicognani A, Baldazzi L, Bergamaschi R, Scarano E, Strocchi S, Nicoletti A, Mencarelli F, Pittalis M, Forabosco A, Cacciari E. Gonadoblastoma in Turner syndrome and Y-chromosome-derived material. Am.1 Med Genet A. 2005; 135:150-4.
19. Chen MJ, Yang JH, Mao TL, Ho HN, Yang YS. Successful pregnancy in a gonadectomized woman with 46,XY gonadal dysgenesis and gonadoblastoma. Fertil Steril.2005; 84:217.
20. Simpson JL. Genetic and phenotypic heterogeneity in ovarian failure:overview of selected candidate genes. Ann N Y Acad Sci.2008; 1135:146-54.
21. Funamoto S, Meili R, Lee S, Parry L, Firtel RA. Spatial and temporal regulation of 3-phosphoinositides by PI3-kinase and PTEN mediates chemotaxis. Cell. 2002;109:611-23.
22. Maduro MR. Pten against premature ovarian failure, the importance of the maternal nucleolus. In the spotlight. Reprod Sci.2008;15:229-30.
23. Goto M, Iwase A, Ando H, Kurotsuchi S, Harata T, Kikkawa F. PTEN and Akt expression during growth of human ovarian follicles. J Assist Reprod Genet. 2007; 24:541-6.
24. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 2004;275:1943-1947.
25. Kurose K, Zhou XP, Araki T, Cannistra SA, Maher ER, Eng C. Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas. Am J Pathol.2001; 158:2097-106.
26. Zhou XP, Kuismanen S, Nystrom-Lahti M, Peltomaki P, Eng C. Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors. Hum Mol Genet.2002; 11:445-50.
27. Reddy P. Liu L, Adhikari D, Jagarlamudi K. Qin, Y S, Shen Y, Du C, Tang W, Hamalainen T, Peng SL, Lan ZJ, Cooney AJ, Huhtaniemi I, Liu K. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science.2008; 319:611-3.
28. Froment P, Bontoux M, Pisselet C, Monget P, Dupont J. PTEN expression in ovine granulosa cells increases during terminal follicular growth. FEBS Lett. 2005; 579:2376-82.
29. Shimizu Y, Kimura F, Takebayashi K, Fujiwara M, Takakura K, Takahashi K. Mutational analysis of the PTEN gene in women with premature ovarian failure.Acta Obstet Gynecol Scand.2009; 88:824-5.
30. Coulam CB. Premature gonadal failure. Fertil Steril.1982; 38:645-55.
31. Coulam CB. Adamson SC, Annegers JF, Incidence of premature ovarian failure. Obstetrics and Gynecology. Obstet Gynecol.1986;67:604-6.
32. Simpson, JL, Rajkovic A. Ovarian differentiation and gonadal failure. Am J Med Genet.1999; 89:186-200.
33. Santoro N. Mechanisms of premature ovarian failure. Ann Endocrinol (Paris).2003; 64:87-92.
34. Toniolo D. X-linked premature ovarian failure:a complex disease. Curr Opin Genet.2006; 16:293-300.
35. Vegetti W, Grazia Tibiletti M, Testa G, de Lauretis Yankowski, Alagna F, Castoldi E, Taborelli M, Motta T, Bolis PF, Dalpra L, Crosignani PG, Inheritance in idiopathic premature ovarian failure:analysis of 71 cases. Hum. Reprod. 1998;13:1796-800.
36. Sherr CJ, Roberts JM. Inhibitors of mammalian Gl cyclin-dependent kinases. Genes Dev.1995;9:1149-63.
37. Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K, Roberts JM, A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in P27(Kipl)-deficient mice. Cell.1996;85:733-44.
38. Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle:a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003; 36:131-49.
39. Bryja V, Cajanek L, Pachernik J, Hall AC, Horvath V, Dvorak P, Hampl A. Abnormal development of mouse embryoid bodies lacking p27Kip cell cycle regulator. Stem Cells.2005;23:965-74.
40. Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor P27. Nat Cell Biol. 1999;1:193-9.
41. Sutterluty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Muller U, Krek W. p45SKP2 promotes P27Kipl degradation and induces S phase in quiescent cells. Nat Cell Biol.1999;1:207-14.
42. Rajareddy S, Reddy P, Du C, Liu L, Jagarlamudi K, Tang W, Shen Y, Berthet C, Peng SL, Kaldis P, Liu K. P27kipl (cyclin-dependent kinase inhibitor IB) controls ovarian development bysuppressing follicle endowment and activation and promoting follicle atresia in mice. Mol. Endocrinol.2007;21:2189-202.
43. Fotovati A, Abu-Ali S, Nakayama K, Nakayama KI. Impaired ovarian development and reduced fertility in female mice deficient in Skp2. 2011;218:668-77.
44. Wang B, Ni F, Li L, Wei Z, Zhu X, Wang J, Cao Y, Ma X. Analysis of cyclin-dependent kinase inhibitor IB mutation in Han Chinese women with premature ovarian failure. Reprod Biomed Online.2010; 21:212-4.
45. Ojeda D, Lakhal B, Fonseca DJ, Braham R, Landolsi H, Mateus HE, Restrepo CM, Elghezal H, Saad A, Laissue P. Sequence analysis of the P27 gene in patients with premature ovarian failure reveals a novel mutation potentially related to the phenotype. Fertil Steril.2011;95:2658-60.
46. Ochalski ME, Engle N, Wakim A, Ravnan BJ, Hoffner L, Rajkovic A, Surti U. Complex X chromosome rearrangement delineated by array comparative genome hybridization in a woman with premature ovarian insufficiency. Fertil Steril. 2011; 95:2433.e9-15.
47. Bione S, Sala C, Manzini C, Arrigo G, Zuffardi O, Banfi S, Borsani G, Jonveaux P. Philippe C, Zuccotti M, Ballabio A, Toniolo D. A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure:evidence for conserved function in oogenesis and implications for human sterility. Am J Hum Genet.1998;62:533-41.
48. Lacombe A, Lee H, Zahed L, Choucair M, Muller JM, Nelson SF, Salameh W, Vilain E. Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure. Am J Hum Genet.2006;79:113-9.
49. Sala C, Arrigo G, Torri G, Martinazzi F, Riva P, Larizza L, Philippe C, Jonveaux P, Sloan F, Labella T, Toniolo D. Eleven X chromosome breakpoints associated with premature ovarian failure (POF) map to a 15-Mb YAC contig spanning Xq21. Genomics.1997 15;40:123-31.
50. Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, Corrigan EC, Simpson JL, Nelson LM. The FMR1 premutation and reproduction. Fertil Steril.2007; 87:456-65.
51. Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA. Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome:two faces of FMR1. Lancet Neurol.2007; 6:45-55.
52. Dixit H, Rao LK, Padmalatha VV, Kanakavalli M, Deenadayal M, Gupta N, Chakrabarty B, Singh L. Missense mutations in the BMP 15 gene are associated with ovarian failure. Hum Genet.2006; 119:408-15.
53. Laissue P, Christin-Maitre S, Touraine P, Kuttenn F, Ritvos O, Aittomaki K, Bourcigaux N, Jacquesson L, Bouchard P, Frydman R, Dewailly D, Reyss AC, Jeffery L, Bachelot A, Massin N, Fellous M, Veitia RA. Mutations and sequence variants in GDF9 and BMP 15 in patients with premature ovarian failure. Eur J Endocrinol.2006; 154:739-44.
54. Aittomaki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila EM, Lehvaslaiho H, Engel AR, Nieschlag E, Huhtaniemi I, de la Chapelle A. Mutation in the follicle-stimulating hormone receptor gene causes,hereditary hypergonadotropic ovarian failure. Cell.1995; 82:959-68.
55. Qin, Y., Choi, Y, Zhao, H., Simpson, J.L., Chen, Z.J., Rajkovic, A. NOBOX homeobox mutation causes premature ovarian failure. Am J Hum Genet. 2007;81:576-81.
56. Zhao H, Chen ZJ, Qin Y, Shi Y, Wang S, Choi Y, Simpson JL, Rajkovic, A. Transcription Factor FIGLA is Mutated in Patients with Premature Ovarian Failure. Am J Hum Genetl.2008; 82:1342-8.
57. Wang J, Wang B, Song J, Suo P, Ni F, Chen B, Ma X, Cao Y. New candidate gene POU5F1 associated with premature ovarian failure in Chinese patients. Reprod Biomed Online.2011; 22:312-6.
58. Mandon-Pepin B, Touraine P, Kuttenn F, Derbois C, Rouxel A, Matsuda F, Nicolas A, Cotinot C, Fellous M. Genetic investigation of four meiotic genes in women with premature ovarian failure. Eur J Endocrinol.2008;158:107-15.
59. Suzumori N, Burns KH, Yan W, Matzuk MM. RFPL4 interacts with oocyte proteins of the ubiquitin-proteasome degradation pathway. Proc Natl Acad Sci U SA.2003; 100:550-5.
60. Qin Y, Zhao H, Kovanci E, Simpson JL, Chen ZJ, Rajkovic A. Mutation analysis of NANOS3 in 80 Chinese and 88 Caucasian women with premature ovarian failure. Fertil Steril.2007; 88:1465-7.
61. Kovanci E, Simpson JL, Amato P, Rohozinski J, Heard MJ, Bishop CE, Carson SA. Oocyte-specific G-protein-coupled receptor 3 (GPR3):no perturbations found in 82 women with premature ovarian failure (first report). Fertil Steril. 2008; 90:1269-71.
62. Qin Y, Zhao H, Kovanci E. Simpson JL, Chen ZJ, Rajkovic A. Analysis of LHX8 mutation in premature ovarian failure. Fertil Steril.2008; 89:1012-4.
63. Zhao Z, Qin Y, Ma J, Zhao H, Li J, Wang L, Ren C, Che L, Chen ZJ. PTEN gene analysis in premature ovarian failure patients. Acta Obstet Gynecol Scand. 2011;90:678-9.
64. Laissue P, Christin-Maitre S, Bouchard P, Fellous M, Veitia RA. Mutations in the NOG gene are not a common cause of nonsyndromic premature ovarian failure. Clin Endocrinol (Oxf).2007; 66:900.
65. Shibanuma K, Tong ZB. Vanderhoof VH, Vanevski K, Nelson LM. Investigation of KIT gene mutations in women with 46.XX spontaneous premature ovarian failure. BMC Womens Health.2002 2: 2:8.
66. Watkins WJ. Umbers AJ, Woad KJ, Harris SE, Winship IM. Gersak K, Shelling AN. Mutational screening of FOXO3A and FOXOIA in women with premature ovarian failure. Fertil Steril.2006; 86:1518-21.
67. Wang HQ, Takakura K, Takebayashi K, Noda Y. Mutational analysis of the mullerian-inhibiting substance gene and its receptor gene in Japanese women with polycystic ovary syndrome and premature ovarian failure. Fertil Steril. 2002; 78:1329-30.
68. Qin Y, Zhao H, Xu J, Shi Y, Li Z, Qiao J, Liu J, Qin C, Ren C, Li J, Chen S, Cao Y; China POF Study Group, Simpson JL, Chen ZJ. Association of 8q22.3 locus in Chinese Han with idiopathic premature ovarian failure (POF). Hum Mol Genet.2012; 21:430-6.
69. Toniolo Li H, Gan W, Lu L, Dong X, Han X, Hu C, Yang Z, Sun L, Bao W, Li P, He M, Sun L, Wang Y, Zhu J, Ning Q, Tang Y, Zhang R, Wen J, Wang D, Zhu X, Guo K, Zuo X, Guo X, Yang H, Zhou X; DIAGRAM Consortium; AGEN-T2D Consortium, Zhang X, Qi L, Loos RJ, Hu FB, Wu T, Liu Y, Liu L, Yang Z, Hu R, Jia W, Ji L, Li Y, Lin X. A Genome-Wide Association Study Identifies GRK5 and RASGRP1 as Type 2 Diabetes Loci in Chinese Hans. Diabetes.2013; 62:291-8.
70. Kang H, Lee SK, Kim MH, Song J, Bae SJ, Kim NK, Lee SH, Kwack K. Parathyroid hormone-responsive Bl gene is associated with premature ovarian failure. Hum Reprod.2008;23:1457-65.
71. Knauff EA, Franke L, van Es MA, van den Berg LH, van der Schouw YT, Laven JS, Lambalk CB, Hoek A, Goverde AJ, Christin-Maitre S, Hsueh AJ, Wijmenga C, Fauser BC; Dutch POF Consortium. Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene. Hum Reprod.2009;24:2372-8.
72. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Mailer J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLFNK:a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet.2007;81: 559-575.
73. Barrett JC, Fry B, Mailer J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics.2005; 21:263-265.
74. Shi YY and He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell. Res.2005; 15:97-98.
75. Mantel N and Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer. Inst.1959; 22:719-748.
76. Sills ES, Harmon KE, Tucker MJ. First reported convergence of premature ovarian failure and cutis marmorata telangiectatica congenita. Fertil. Steril.2002; 78:1314-1316.
77. Tupler R, Barbierato L, Larizza D, Sampaolo P, Piovella F, Maraschio P. Balanced autosomal translocations and ovarian dysgenesis. Hum. Genet.1994; 94:171-176.
78. Aboura A, Dupas C, Tachdjian G, Portnoi MF, Bourcigaux N, Dewailly D, Frydman R, Fauser B, Ronci-Chaix N, Donadille B, Bouchard P, Christin-Maitre S. Array comparative genomic hybridization profiling analysis reveals deoxyribonucleic acid copy number variations associated with premature ovarian failure. J. Clin. Endocrinol. Metab.2009; 94:4540-4546.
79. Ledig S, Ropke A, Wieacker P. Copy number variants in premature ovarian failure and ovarian dysgenesis. Sex. Dev.,2010:4:225-232.
80. Cheni Kwok, Polly A. Weller, Silvana Guioli, Jamie W. Foster, Sahar Mansour, Orsetta Zuffardi, Hope H. Punnett, Marina A. Dominguez-Steglich, J. David Brook, Ian D. Young, Peter N. Goodfellow, Alan J. Schafer. Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. Am. J. Hum. Genet.1995; 57:1028-1036.
81. Huang B, Wang S, Ning Y, Lamb AN, Bartley J. Autosomal XX sex reversal caused by duplication of SOX9. Am. J. Med. Genet.,1999:87, 349-353.
82. Qin Y and Bishop CE. Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry. Hum. Mol. Genet.2005; 14: 1221-1229.
83. Leipoldt M, Erdel M. Bien-Willner G.A., Smyk, M., Theurl. M., Yatsenko, S.A., Lupski, J.R., Lane, A.H.. Shanske, A.L., Stankiewicz, P., et al. Two novel translocation breakpoints upstream of SOX9 define borders of the proximal and distal breakpoint cluster region in campomelic dysplasia. Clin. Genet.2007; 71:67-75.
84. He C, Kraft P, Chasman,DI, Buring JE, Chen C, Hankinson SE, Pare G, Chanock, S, Ridker PM, Hunter DJ. A large-scale candidate gene association study of age at menarche and age at natural menopause. Hum. Genet. 2010; 5:515-527.
85. He C, Kraft P, Chen C, Buring JE, Pare G, Hankinson SE, Chanock SJ, Ridker PM, Hunter DJ, Chasman DI. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat. Genet.2009; 6:724-728.
86. Anna Murray, Claire E. Bennett, John R.B. Perry, Michael N. Weedon, ReproGen Consortium, Patricia A. Jacobs, Danielle H. Morris, Nicholas Orr, Minouk J. Schoemaker, Michael Jones, Alan Ashworth, Anthony J. Swerdlow Common genetic variants are significant risk factors for early menopause:results from the Breakthrough Generations Study. Hum. Mol. Genet. 2011; 1:186-192.
87. Lisette Stolk, Guangju Zhai, Joyce B J van Meurs, Michael M P J Verbiest, Jenny A Visser, Karol Estrada, Fernando Rivadeneira, Frances M Williams, Lynn Cherkas, Panos Deloukas, Nicole Soranzo, Jules J de Keyzer, Victor J M Pop, Paul Lips, Corinne E I Lebrun, Yvonne T van der Schouw, Diederick E Grobbee, Jacqueline Witteman, Albert Hofman, Huibert A P Pols, Joop S E Laven, Tim D Spector, Andre G Uitterlinden. Loci at chromosomes 13,19 and 20 influence age at natural menopause. Nat. Genet.2009; 6:645-647.
88. Suchanecka A, Grzywacz A, Samochowiec J. ANKK1 gene in psychiatry. Psychiatr Pol.2011;45: 349-56.
89. Gougeon A, Chainy GB. Morphometric studies of small follicles in ovaries of women at different ages. J Reprod Fertil.1987; 81:433-442.
90. Hirshfield AN. Development of follicles in the mammalian ovary. Int RevCytol. 1991; 124:43-101.
91. McGee EA, Hsueh AJ.I nitial and cyclic recruitment of ovarian follicles. Endocr Rev.2000; 21:200-214.
92. Bachelot A, Rouxel A, Massin N, Dulon J, Courtillot C, Matuchansky C, Badachi Y, Fortin A, Paniel B, Lecuru F, Lefrere-Belda MA, Constancis E, Thibault E, Meduri G, Guiochon-Mantel A, Misrahi M, Kuttenn F, Touraine P; POF-GIS Study Group. Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure. Eur J Endocrinol. 2009; 161:179-87.
93. Adhikari D, Liu K. Molecular mechanisms underlying the activation of mammalian primordial follicles. Endocr Rev 30:438-464. Eppig JJ, O'Brien MJ. Development in vitro of mouse oocytes from primordial follicles. Biol Reprod. 2009; 54:197-207.
94. Jagarlamudi K, Liu L, Adhikari D, Reddy P, Idahl A, Ottander U, Lundin E, Liu K. Oocyte specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation. PLoS One. 2009;4:e6186.
95. Li J, Kawamura K, Cheng Y, Liu S, Klein C, Liu S, Duan EK, Hsueh AJ. Activation of dormant ovarian follicles to generate mature eggs. Proc Natl Acad Sci U S A.2010; 107:10280-10284.
96. Kurose K, Zhou XP, Araki T, Cannistra SA, Maher ER, Eng C. Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin Dl expression, in primary epithelial ovarian carcinomas. Am J Pathol.2001;158:2097-106.
97. Zhou XP, Kuismanen S, Nystrom-Lahti M, Peltomaki P, Eng C. Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors. Hum Mol Genet.2002 15; 11:445-50.
98. Reddy P, Liu L, Adhikari D, Jagarlamudi K, Rajareddy S, Shen Y, Du C, Tang W, Hamalainen T, Peng SL, Lan ZJ, Cooney AJ, Huhtaniemi I, Liu K. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science.2008; 319:611-3.
99. Schmid AC, Byrne RD, Vilar R. Woscholski R. Bisperoxovanadium compounds are potent PTEN inhibitors. BS Lett.2004;566:35-8.
100. Jeruss JS, Woodruff TK. Preservation of fertility in patients with cancer.N Engl J Med.2009; 360:902-911.
101.Hovatta O. Cryopreservation and culture of human ovarian cortical tissue containing early follicles. Eur J Obstet Gynecol Reprod Biol.2004; 113 Suppl 1:S50-4.
102. Rosendahl M, Schmidt KT, Ernst E, Rasmussen PE, Loft A, Byskov AG, Andersen AN, Andersen CY.. Cryopreservation of ovarian tissue for a decade in Denmark:a view of the technique. Reprod Biomed Online.2011; 22:162-171.
103. Eppig JJ, O'Brien MJ. Development in vitro of mouse oocytes from primordial follicles. Biol Reprod.1996; 54:197-207.
104. Anderson RA, Wallace WH, Baird DT. Ovarian cryopreservation for fertility preservation:indications and outcomes. Reproduction.2008; 136:681-689.
105. Kim SS. Assessment of long term endocrine function after transplantation of frozen-thawed human ovarian tissue to the heterotopic site:10 year longitudinal follow-up study. Assist Reprod Genet.2012; 29:489-93.
106. Fan HY, Liu Z, Cahill N, Richards JS. Targeted disruption of Pten in ovarian granulosa cells enhances ovulation and extends the life span of luteal cells. Mol Endocrinol.2008; 22:2128-2140.
107. Sunkara SK, Coomarasamy A, Arlt W, Bhattacharya S. Should androgen supplementation be used for poor ovarian response in IVF? Hum Reprod.2012;27:637-40.
108. Kwee J, EltingMW, Schats R, Bezemer PD, Lambalk CB, Schoemaker J. Comparison of endocrine tests with respect to their predictive value on the outcome of ovarian hyperstimulation in IVF treatment:results of a prospective randomized study. Hum Reprod.2003; 18:1422-7.
109. Steckler T, Wang J, Bartol FF, Roy SK, Padmanabhan V: Fetal programming: prenatal testosterone treatment causes intrauterine growth retardation,reduces ovarian reserve and increases ovarian follicular recruitment.Endocrinology.2005; 146:3185-3193.
110. Vendola K, Zhou J, Wang J, Famuyiwa OA, Bievre M, Bondy CA: Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol Reprod.1999; 61:353-357.
111. Vendola KA, Zhou J, Adesanya OO, Weil SJ, Bondy CA:Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest.1998; 101:2622-2629.
112. Barad D, Brill H, Gleicher N:Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function. J Assist Reprod Genet.2007; 24:629-634.
113. Fabregues F, Penarrubia J, Creus M, Manau D, Casals G, Carmona F, Balasch J: Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients:a randomized, clinical trial. Hum Reprod.2009; 24:349-359.
114. Mamas L, Mamas E:Premature ovarian failure and dehydroepiandrosterone. Fertil Steril.2009; 91:644-646.
115. Balasch J, Fabregues F, Penarrubia J, Carmona F, Casamitjana R, Creus M, Manau D, Casals G, Vanrell JA:Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor responder IVF patients with normal basal concentrations of FSH. Hum Reprod.2006; 21:1884-93.
116. Puissant F, Van Rysselberge M, Barlow P, Deweze J, Leroy F:Embryo scoring as a prognostic tool in IVF treatment. Hum Reprod.1987; 2:705-708.
117. Frattarelli JL, Peterson EH. Effect of androgen levels on in vitro fertilization cycles. Fertil Steril.2004; 81:1713-4.
118. Barbieri RL, Sluss PM, Powers RD, McShane PM, Vitonis A, Ginsburg E, Cramer DC. Association of body mass index, age, and cigarette smoking with serum testosterone levels in cycling women undergoing in vitro fertilization. Fertil Steril.2005; 83:302-8.
2. Kalantaridou SN, Davis SR, Nelson LM. Premature ovarian failure.Endocrinol Metab Clin North Am.1998;27:989-1006.
3. Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update. 2005;11:391-410.
4. Christin-Maitre S, Pasquier M, Donadille B, Bouchard P. Premature ovarian failure. Ann Endocrinol (Paris).2006;67:557-66.
5. Portnoi MF, Aboura A, Tachdjian G, Bouchard P, Dewailly D, Bourcigaux N, Frydman R, Reyss AC, Brisset S, Christin-Maitre S. Molecular cytogenetic studies of Xq critical regions in premature ovarian failure patients. Hum Reprod. 2006; 21:2329-34.
6. Zinn AR. The X chromosome and the ovary. Soc Gynecol Investig. 2001;8:S34-6.
7. Devi A, Benn PA. X-Chromosome abnormalities in women with premature ovarian failure. J Reprod Med 1999; 44:321.
8. Bakalov VK, Axelrod L, Baron J, Hanton L, Nelson LM, Reynolds JC, Hill S, Troendle J, Bondy CA. Selective reduction in cortical bone mineral density in turner syndrome independent of ovarian hormone deficiency. J Clin Endocrinol Metab.2003;88:5717-22.
9. 李程.程茜Turner综合征临床表现的遗传学基础研究进展.中国实用儿科杂志,2007:546-548.
10. Yaron Y, Ochshorn Y, Amit A, Yovel I, Kogosowki A, Lessing JB. Patients with Turner's syndrome may have an inherent endometrial abnormality affecting receptivity in oocyte donation. Fertil Steril.1996; 65:1249-52.
11. Blair J, Tolmie J, Hollman AS, Donaldson MD. Phenotype, ovarian function, and growth in patients with 45, X/47, ⅩⅩⅩ Turner mosaicism:Implications for prenatal counseling and estrogen therapy at puberty. J Pediatr.2001;139:724-8.
12. Mazzanti L, Cicognani A, Baldazzi L, Bergamaschi R, Scarano E, Strocchi S, Nicoletti A, Mencarelli F, Pittalis M, Forabosco A, Cacciari E. Gonadoblastoma in Turner syndrome and Y-chromosome-derived material. Am J Med Genet A. 2005;135:150-4.
13. Hanson L, Bryman I, Janson PO, Jakobsen AM, Hanson C. Fluorescence in situ hybridization analysis and ovarian histology of women with Turner syndrome presenting with Y-chromosomal material:a correlation between oral epithelial cells, lymphocytes and ovarian tissue. Hereditas.2002;137:1-6.
14. Rooman RP, Van Driessche K, Du Caju MV. Growth and ovarian function in girls with 48, XXXX karyotype--patient report and review of the literature. J Pediatr Endocrinol Metab.2002; 15:1051-5.
15. Holland CM.47, XXX in an adolescent with premature ovarian failure and autoimmune disease. J Pediatr Adolesc Gynecol.2001; 14:77-80.
16. Holland CM.47, XXX in an adolescent with premature ovarian failure and autoimmune disease. J Pediatr Adolesc Gynecol. J Pediatr Adolesc Gynecol. 2000; 13:93..
17. Goswami R, Goswami D, Kabra M, Gupta N, Dubey S, Dadhwal V. Prevalence of the triple X syndrome in phenotypically normal women with premature ovarian failure and its association with autoimmune thyroid disorders. Fertil Steril.2003;80:1052-4.
18. Mazzanti L, Cicognani A, Baldazzi L, Bergamaschi R, Scarano E, Strocchi S, Nicoletti A, Mencarelli F, Pittalis M, Forabosco A, Cacciari E. Gonadoblastoma in Turner syndrome and Y-chromosome-derived material. Am.1 Med Genet A. 2005; 135:150-4.
19. Chen MJ, Yang JH, Mao TL, Ho HN, Yang YS. Successful pregnancy in a gonadectomized woman with 46,XY gonadal dysgenesis and gonadoblastoma. Fertil Steril.2005; 84:217.
20. Simpson JL. Genetic and phenotypic heterogeneity in ovarian failure:overview of selected candidate genes. Ann N Y Acad Sci.2008; 1135:146-54.
21. Funamoto S, Meili R, Lee S, Parry L, Firtel RA. Spatial and temporal regulation of 3-phosphoinositides by PI3-kinase and PTEN mediates chemotaxis. Cell. 2002;109:611-23.
22. Maduro MR. Pten against premature ovarian failure, the importance of the maternal nucleolus. In the spotlight. Reprod Sci.2008;15:229-30.
23. Goto M, Iwase A, Ando H, Kurotsuchi S, Harata T, Kikkawa F. PTEN and Akt expression during growth of human ovarian follicles. J Assist Reprod Genet. 2007; 24:541-6.
24. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 2004;275:1943-1947.
25. Kurose K, Zhou XP, Araki T, Cannistra SA, Maher ER, Eng C. Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas. Am J Pathol.2001; 158:2097-106.
26. Zhou XP, Kuismanen S, Nystrom-Lahti M, Peltomaki P, Eng C. Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors. Hum Mol Genet.2002; 11:445-50.
27. Reddy P. Liu L, Adhikari D, Jagarlamudi K. Qin, Y S, Shen Y, Du C, Tang W, Hamalainen T, Peng SL, Lan ZJ, Cooney AJ, Huhtaniemi I, Liu K. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science.2008; 319:611-3.
28. Froment P, Bontoux M, Pisselet C, Monget P, Dupont J. PTEN expression in ovine granulosa cells increases during terminal follicular growth. FEBS Lett. 2005; 579:2376-82.
29. Shimizu Y, Kimura F, Takebayashi K, Fujiwara M, Takakura K, Takahashi K. Mutational analysis of the PTEN gene in women with premature ovarian failure.Acta Obstet Gynecol Scand.2009; 88:824-5.
30. Coulam CB. Premature gonadal failure. Fertil Steril.1982; 38:645-55.
31. Coulam CB. Adamson SC, Annegers JF, Incidence of premature ovarian failure. Obstetrics and Gynecology. Obstet Gynecol.1986;67:604-6.
32. Simpson, JL, Rajkovic A. Ovarian differentiation and gonadal failure. Am J Med Genet.1999; 89:186-200.
33. Santoro N. Mechanisms of premature ovarian failure. Ann Endocrinol (Paris).2003; 64:87-92.
34. Toniolo D. X-linked premature ovarian failure:a complex disease. Curr Opin Genet.2006; 16:293-300.
35. Vegetti W, Grazia Tibiletti M, Testa G, de Lauretis Yankowski, Alagna F, Castoldi E, Taborelli M, Motta T, Bolis PF, Dalpra L, Crosignani PG, Inheritance in idiopathic premature ovarian failure:analysis of 71 cases. Hum. Reprod. 1998;13:1796-800.
36. Sherr CJ, Roberts JM. Inhibitors of mammalian Gl cyclin-dependent kinases. Genes Dev.1995;9:1149-63.
37. Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K, Roberts JM, A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in P27(Kipl)-deficient mice. Cell.1996;85:733-44.
38. Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle:a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003; 36:131-49.
39. Bryja V, Cajanek L, Pachernik J, Hall AC, Horvath V, Dvorak P, Hampl A. Abnormal development of mouse embryoid bodies lacking p27Kip cell cycle regulator. Stem Cells.2005;23:965-74.
40. Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor P27. Nat Cell Biol. 1999;1:193-9.
41. Sutterluty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Muller U, Krek W. p45SKP2 promotes P27Kipl degradation and induces S phase in quiescent cells. Nat Cell Biol.1999;1:207-14.
42. Rajareddy S, Reddy P, Du C, Liu L, Jagarlamudi K, Tang W, Shen Y, Berthet C, Peng SL, Kaldis P, Liu K. P27kipl (cyclin-dependent kinase inhibitor IB) controls ovarian development bysuppressing follicle endowment and activation and promoting follicle atresia in mice. Mol. Endocrinol.2007;21:2189-202.
43. Fotovati A, Abu-Ali S, Nakayama K, Nakayama KI. Impaired ovarian development and reduced fertility in female mice deficient in Skp2. 2011;218:668-77.
44. Wang B, Ni F, Li L, Wei Z, Zhu X, Wang J, Cao Y, Ma X. Analysis of cyclin-dependent kinase inhibitor IB mutation in Han Chinese women with premature ovarian failure. Reprod Biomed Online.2010; 21:212-4.
45. Ojeda D, Lakhal B, Fonseca DJ, Braham R, Landolsi H, Mateus HE, Restrepo CM, Elghezal H, Saad A, Laissue P. Sequence analysis of the P27 gene in patients with premature ovarian failure reveals a novel mutation potentially related to the phenotype. Fertil Steril.2011;95:2658-60.
46. Ochalski ME, Engle N, Wakim A, Ravnan BJ, Hoffner L, Rajkovic A, Surti U. Complex X chromosome rearrangement delineated by array comparative genome hybridization in a woman with premature ovarian insufficiency. Fertil Steril. 2011; 95:2433.e9-15.
47. Bione S, Sala C, Manzini C, Arrigo G, Zuffardi O, Banfi S, Borsani G, Jonveaux P. Philippe C, Zuccotti M, Ballabio A, Toniolo D. A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure:evidence for conserved function in oogenesis and implications for human sterility. Am J Hum Genet.1998;62:533-41.
48. Lacombe A, Lee H, Zahed L, Choucair M, Muller JM, Nelson SF, Salameh W, Vilain E. Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure. Am J Hum Genet.2006;79:113-9.
49. Sala C, Arrigo G, Torri G, Martinazzi F, Riva P, Larizza L, Philippe C, Jonveaux P, Sloan F, Labella T, Toniolo D. Eleven X chromosome breakpoints associated with premature ovarian failure (POF) map to a 15-Mb YAC contig spanning Xq21. Genomics.1997 15;40:123-31.
50. Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, Corrigan EC, Simpson JL, Nelson LM. The FMR1 premutation and reproduction. Fertil Steril.2007; 87:456-65.
51. Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA. Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome:two faces of FMR1. Lancet Neurol.2007; 6:45-55.
52. Dixit H, Rao LK, Padmalatha VV, Kanakavalli M, Deenadayal M, Gupta N, Chakrabarty B, Singh L. Missense mutations in the BMP 15 gene are associated with ovarian failure. Hum Genet.2006; 119:408-15.
53. Laissue P, Christin-Maitre S, Touraine P, Kuttenn F, Ritvos O, Aittomaki K, Bourcigaux N, Jacquesson L, Bouchard P, Frydman R, Dewailly D, Reyss AC, Jeffery L, Bachelot A, Massin N, Fellous M, Veitia RA. Mutations and sequence variants in GDF9 and BMP 15 in patients with premature ovarian failure. Eur J Endocrinol.2006; 154:739-44.
54. Aittomaki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila EM, Lehvaslaiho H, Engel AR, Nieschlag E, Huhtaniemi I, de la Chapelle A. Mutation in the follicle-stimulating hormone receptor gene causes,hereditary hypergonadotropic ovarian failure. Cell.1995; 82:959-68.
55. Qin, Y., Choi, Y, Zhao, H., Simpson, J.L., Chen, Z.J., Rajkovic, A. NOBOX homeobox mutation causes premature ovarian failure. Am J Hum Genet. 2007;81:576-81.
56. Zhao H, Chen ZJ, Qin Y, Shi Y, Wang S, Choi Y, Simpson JL, Rajkovic, A. Transcription Factor FIGLA is Mutated in Patients with Premature Ovarian Failure. Am J Hum Genetl.2008; 82:1342-8.
57. Wang J, Wang B, Song J, Suo P, Ni F, Chen B, Ma X, Cao Y. New candidate gene POU5F1 associated with premature ovarian failure in Chinese patients. Reprod Biomed Online.2011; 22:312-6.
58. Mandon-Pepin B, Touraine P, Kuttenn F, Derbois C, Rouxel A, Matsuda F, Nicolas A, Cotinot C, Fellous M. Genetic investigation of four meiotic genes in women with premature ovarian failure. Eur J Endocrinol.2008;158:107-15.
59. Suzumori N, Burns KH, Yan W, Matzuk MM. RFPL4 interacts with oocyte proteins of the ubiquitin-proteasome degradation pathway. Proc Natl Acad Sci U SA.2003; 100:550-5.
60. Qin Y, Zhao H, Kovanci E, Simpson JL, Chen ZJ, Rajkovic A. Mutation analysis of NANOS3 in 80 Chinese and 88 Caucasian women with premature ovarian failure. Fertil Steril.2007; 88:1465-7.
61. Kovanci E, Simpson JL, Amato P, Rohozinski J, Heard MJ, Bishop CE, Carson SA. Oocyte-specific G-protein-coupled receptor 3 (GPR3):no perturbations found in 82 women with premature ovarian failure (first report). Fertil Steril. 2008; 90:1269-71.
62. Qin Y, Zhao H, Kovanci E. Simpson JL, Chen ZJ, Rajkovic A. Analysis of LHX8 mutation in premature ovarian failure. Fertil Steril.2008; 89:1012-4.
63. Zhao Z, Qin Y, Ma J, Zhao H, Li J, Wang L, Ren C, Che L, Chen ZJ. PTEN gene analysis in premature ovarian failure patients. Acta Obstet Gynecol Scand. 2011;90:678-9.
64. Laissue P, Christin-Maitre S, Bouchard P, Fellous M, Veitia RA. Mutations in the NOG gene are not a common cause of nonsyndromic premature ovarian failure. Clin Endocrinol (Oxf).2007; 66:900.
65. Shibanuma K, Tong ZB. Vanderhoof VH, Vanevski K, Nelson LM. Investigation of KIT gene mutations in women with 46.XX spontaneous premature ovarian failure. BMC Womens Health.2002 2: 2:8.
66. Watkins WJ. Umbers AJ, Woad KJ, Harris SE, Winship IM. Gersak K, Shelling AN. Mutational screening of FOXO3A and FOXOIA in women with premature ovarian failure. Fertil Steril.2006; 86:1518-21.
67. Wang HQ, Takakura K, Takebayashi K, Noda Y. Mutational analysis of the mullerian-inhibiting substance gene and its receptor gene in Japanese women with polycystic ovary syndrome and premature ovarian failure. Fertil Steril. 2002; 78:1329-30.
68. Qin Y, Zhao H, Xu J, Shi Y, Li Z, Qiao J, Liu J, Qin C, Ren C, Li J, Chen S, Cao Y; China POF Study Group, Simpson JL, Chen ZJ. Association of 8q22.3 locus in Chinese Han with idiopathic premature ovarian failure (POF). Hum Mol Genet.2012; 21:430-6.
69. Toniolo Li H, Gan W, Lu L, Dong X, Han X, Hu C, Yang Z, Sun L, Bao W, Li P, He M, Sun L, Wang Y, Zhu J, Ning Q, Tang Y, Zhang R, Wen J, Wang D, Zhu X, Guo K, Zuo X, Guo X, Yang H, Zhou X; DIAGRAM Consortium; AGEN-T2D Consortium, Zhang X, Qi L, Loos RJ, Hu FB, Wu T, Liu Y, Liu L, Yang Z, Hu R, Jia W, Ji L, Li Y, Lin X. A Genome-Wide Association Study Identifies GRK5 and RASGRP1 as Type 2 Diabetes Loci in Chinese Hans. Diabetes.2013; 62:291-8.
70. Kang H, Lee SK, Kim MH, Song J, Bae SJ, Kim NK, Lee SH, Kwack K. Parathyroid hormone-responsive Bl gene is associated with premature ovarian failure. Hum Reprod.2008;23:1457-65.
71. Knauff EA, Franke L, van Es MA, van den Berg LH, van der Schouw YT, Laven JS, Lambalk CB, Hoek A, Goverde AJ, Christin-Maitre S, Hsueh AJ, Wijmenga C, Fauser BC; Dutch POF Consortium. Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene. Hum Reprod.2009;24:2372-8.
72. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Mailer J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLFNK:a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet.2007;81: 559-575.
73. Barrett JC, Fry B, Mailer J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics.2005; 21:263-265.
74. Shi YY and He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell. Res.2005; 15:97-98.
75. Mantel N and Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer. Inst.1959; 22:719-748.
76. Sills ES, Harmon KE, Tucker MJ. First reported convergence of premature ovarian failure and cutis marmorata telangiectatica congenita. Fertil. Steril.2002; 78:1314-1316.
77. Tupler R, Barbierato L, Larizza D, Sampaolo P, Piovella F, Maraschio P. Balanced autosomal translocations and ovarian dysgenesis. Hum. Genet.1994; 94:171-176.
78. Aboura A, Dupas C, Tachdjian G, Portnoi MF, Bourcigaux N, Dewailly D, Frydman R, Fauser B, Ronci-Chaix N, Donadille B, Bouchard P, Christin-Maitre S. Array comparative genomic hybridization profiling analysis reveals deoxyribonucleic acid copy number variations associated with premature ovarian failure. J. Clin. Endocrinol. Metab.2009; 94:4540-4546.
79. Ledig S, Ropke A, Wieacker P. Copy number variants in premature ovarian failure and ovarian dysgenesis. Sex. Dev.,2010:4:225-232.
80. Cheni Kwok, Polly A. Weller, Silvana Guioli, Jamie W. Foster, Sahar Mansour, Orsetta Zuffardi, Hope H. Punnett, Marina A. Dominguez-Steglich, J. David Brook, Ian D. Young, Peter N. Goodfellow, Alan J. Schafer. Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. Am. J. Hum. Genet.1995; 57:1028-1036.
81. Huang B, Wang S, Ning Y, Lamb AN, Bartley J. Autosomal XX sex reversal caused by duplication of SOX9. Am. J. Med. Genet.,1999:87, 349-353.
82. Qin Y and Bishop CE. Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry. Hum. Mol. Genet.2005; 14: 1221-1229.
83. Leipoldt M, Erdel M. Bien-Willner G.A., Smyk, M., Theurl. M., Yatsenko, S.A., Lupski, J.R., Lane, A.H.. Shanske, A.L., Stankiewicz, P., et al. Two novel translocation breakpoints upstream of SOX9 define borders of the proximal and distal breakpoint cluster region in campomelic dysplasia. Clin. Genet.2007; 71:67-75.
84. He C, Kraft P, Chasman,DI, Buring JE, Chen C, Hankinson SE, Pare G, Chanock, S, Ridker PM, Hunter DJ. A large-scale candidate gene association study of age at menarche and age at natural menopause. Hum. Genet. 2010; 5:515-527.
85. He C, Kraft P, Chen C, Buring JE, Pare G, Hankinson SE, Chanock SJ, Ridker PM, Hunter DJ, Chasman DI. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat. Genet.2009; 6:724-728.
86. Anna Murray, Claire E. Bennett, John R.B. Perry, Michael N. Weedon, ReproGen Consortium, Patricia A. Jacobs, Danielle H. Morris, Nicholas Orr, Minouk J. Schoemaker, Michael Jones, Alan Ashworth, Anthony J. Swerdlow Common genetic variants are significant risk factors for early menopause:results from the Breakthrough Generations Study. Hum. Mol. Genet. 2011; 1:186-192.
87. Lisette Stolk, Guangju Zhai, Joyce B J van Meurs, Michael M P J Verbiest, Jenny A Visser, Karol Estrada, Fernando Rivadeneira, Frances M Williams, Lynn Cherkas, Panos Deloukas, Nicole Soranzo, Jules J de Keyzer, Victor J M Pop, Paul Lips, Corinne E I Lebrun, Yvonne T van der Schouw, Diederick E Grobbee, Jacqueline Witteman, Albert Hofman, Huibert A P Pols, Joop S E Laven, Tim D Spector, Andre G Uitterlinden. Loci at chromosomes 13,19 and 20 influence age at natural menopause. Nat. Genet.2009; 6:645-647.
88. Suchanecka A, Grzywacz A, Samochowiec J. ANKK1 gene in psychiatry. Psychiatr Pol.2011;45: 349-56.
89. Gougeon A, Chainy GB. Morphometric studies of small follicles in ovaries of women at different ages. J Reprod Fertil.1987; 81:433-442.
90. Hirshfield AN. Development of follicles in the mammalian ovary. Int RevCytol. 1991; 124:43-101.
91. McGee EA, Hsueh AJ.I nitial and cyclic recruitment of ovarian follicles. Endocr Rev.2000; 21:200-214.
92. Bachelot A, Rouxel A, Massin N, Dulon J, Courtillot C, Matuchansky C, Badachi Y, Fortin A, Paniel B, Lecuru F, Lefrere-Belda MA, Constancis E, Thibault E, Meduri G, Guiochon-Mantel A, Misrahi M, Kuttenn F, Touraine P; POF-GIS Study Group. Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure. Eur J Endocrinol. 2009; 161:179-87.
93. Adhikari D, Liu K. Molecular mechanisms underlying the activation of mammalian primordial follicles. Endocr Rev 30:438-464. Eppig JJ, O'Brien MJ. Development in vitro of mouse oocytes from primordial follicles. Biol Reprod. 2009; 54:197-207.
94. Jagarlamudi K, Liu L, Adhikari D, Reddy P, Idahl A, Ottander U, Lundin E, Liu K. Oocyte specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation. PLoS One. 2009;4:e6186.
95. Li J, Kawamura K, Cheng Y, Liu S, Klein C, Liu S, Duan EK, Hsueh AJ. Activation of dormant ovarian follicles to generate mature eggs. Proc Natl Acad Sci U S A.2010; 107:10280-10284.
96. Kurose K, Zhou XP, Araki T, Cannistra SA, Maher ER, Eng C. Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin Dl expression, in primary epithelial ovarian carcinomas. Am J Pathol.2001;158:2097-106.
97. Zhou XP, Kuismanen S, Nystrom-Lahti M, Peltomaki P, Eng C. Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors. Hum Mol Genet.2002 15; 11:445-50.
98. Reddy P, Liu L, Adhikari D, Jagarlamudi K, Rajareddy S, Shen Y, Du C, Tang W, Hamalainen T, Peng SL, Lan ZJ, Cooney AJ, Huhtaniemi I, Liu K. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science.2008; 319:611-3.
99. Schmid AC, Byrne RD, Vilar R. Woscholski R. Bisperoxovanadium compounds are potent PTEN inhibitors. BS Lett.2004;566:35-8.
100. Jeruss JS, Woodruff TK. Preservation of fertility in patients with cancer.N Engl J Med.2009; 360:902-911.
101.Hovatta O. Cryopreservation and culture of human ovarian cortical tissue containing early follicles. Eur J Obstet Gynecol Reprod Biol.2004; 113 Suppl 1:S50-4.
102. Rosendahl M, Schmidt KT, Ernst E, Rasmussen PE, Loft A, Byskov AG, Andersen AN, Andersen CY.. Cryopreservation of ovarian tissue for a decade in Denmark:a view of the technique. Reprod Biomed Online.2011; 22:162-171.
103. Eppig JJ, O'Brien MJ. Development in vitro of mouse oocytes from primordial follicles. Biol Reprod.1996; 54:197-207.
104. Anderson RA, Wallace WH, Baird DT. Ovarian cryopreservation for fertility preservation:indications and outcomes. Reproduction.2008; 136:681-689.
105. Kim SS. Assessment of long term endocrine function after transplantation of frozen-thawed human ovarian tissue to the heterotopic site:10 year longitudinal follow-up study. Assist Reprod Genet.2012; 29:489-93.
106. Fan HY, Liu Z, Cahill N, Richards JS. Targeted disruption of Pten in ovarian granulosa cells enhances ovulation and extends the life span of luteal cells. Mol Endocrinol.2008; 22:2128-2140.
107. Sunkara SK, Coomarasamy A, Arlt W, Bhattacharya S. Should androgen supplementation be used for poor ovarian response in IVF? Hum Reprod.2012;27:637-40.
108. Kwee J, EltingMW, Schats R, Bezemer PD, Lambalk CB, Schoemaker J. Comparison of endocrine tests with respect to their predictive value on the outcome of ovarian hyperstimulation in IVF treatment:results of a prospective randomized study. Hum Reprod.2003; 18:1422-7.
109. Steckler T, Wang J, Bartol FF, Roy SK, Padmanabhan V: Fetal programming: prenatal testosterone treatment causes intrauterine growth retardation,reduces ovarian reserve and increases ovarian follicular recruitment.Endocrinology.2005; 146:3185-3193.
110. Vendola K, Zhou J, Wang J, Famuyiwa OA, Bievre M, Bondy CA: Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol Reprod.1999; 61:353-357.
111. Vendola KA, Zhou J, Adesanya OO, Weil SJ, Bondy CA:Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest.1998; 101:2622-2629.
112. Barad D, Brill H, Gleicher N:Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function. J Assist Reprod Genet.2007; 24:629-634.
113. Fabregues F, Penarrubia J, Creus M, Manau D, Casals G, Carmona F, Balasch J: Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients:a randomized, clinical trial. Hum Reprod.2009; 24:349-359.
114. Mamas L, Mamas E:Premature ovarian failure and dehydroepiandrosterone. Fertil Steril.2009; 91:644-646.
115. Balasch J, Fabregues F, Penarrubia J, Carmona F, Casamitjana R, Creus M, Manau D, Casals G, Vanrell JA:Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor responder IVF patients with normal basal concentrations of FSH. Hum Reprod.2006; 21:1884-93.
116. Puissant F, Van Rysselberge M, Barlow P, Deweze J, Leroy F:Embryo scoring as a prognostic tool in IVF treatment. Hum Reprod.1987; 2:705-708.
117. Frattarelli JL, Peterson EH. Effect of androgen levels on in vitro fertilization cycles. Fertil Steril.2004; 81:1713-4.
118. Barbieri RL, Sluss PM, Powers RD, McShane PM, Vitonis A, Ginsburg E, Cramer DC. Association of body mass index, age, and cigarette smoking with serum testosterone levels in cycling women undergoing in vitro fertilization. Fertil Steril.2005; 83:302-8.