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Hess MK, Mersha A, Ference SS, Nafziger SR, Keane JA, Fuller AM, Kurz SG, Sutton CM, Spangler ML, Petersen JL, Cupp AS. Puberty classifications in beef heifers are moderately to highly heritable and associated with candidate genes related to cyclicity and timing of puberty. Front Genet 2024; 15:1405456. [PMID: 38939530 PMCID: PMC11208629 DOI: 10.3389/fgene.2024.1405456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/22/2024] [Accepted: 05/23/2024] [Indexed: 06/29/2024] Open
Abstract
Introduction: Pubertal attainment is critical to reproductive longevity in heifers. Previously, four heifer pubertal classifications were identified according to attainment of blood plasma progesterone concentrations > 1 ng/ml: 1) Early; 2) Typical; 3) Start-Stop; and 4) Non-Cycling. Early and Typical heifers initiated and maintained cyclicity, Start-Stop started and then stopped cyclicity and Non-Cycling never initiated cyclicity. Start-Stop heifers segregated into Start-Stop-Discontinuous (SSD) or Start-Stop-Start (SSS), with SSD having similar phenotypes to Non-Cycling and SSS to Typical heifers. We hypothesized that these pubertal classifications are heritable, and loci associated with pubertal classifications could be identified by genome wide association studies (GWAS). Methods: Heifers (n = 532; 2017 - 2022) genotyped on the Illumina Bovine SNP50 v2 or GGP Bovine 100K SNP panels were used for variant component estimation and GWAS. Heritability was estimated using a univariate Bayesian animal model. Results: When considering pubertal classifications: Early, Typical, SSS, SSD, and Non-Cycling, pubertal class was moderately heritable (0.38 ± 0.08). However, when heifers who initiated and maintained cyclicity were compared to those that did not cycle (Early+Typical vs. SSD+Non-Cycling) heritability was greater (0.59 ± 0.19). A GWAS did not identify single nucleotide polymorphisms (SNPs) significantly associated with pubertal classifications, indicating puberty is a polygenic trait. A candidate gene approach was used, which fitted SNPs within or nearby a set of 71 candidate genes previously associated with puberty, PCOS, cyclicity, regulation of hormone secretion, signal transduction, and methylation. Eight genes/regions were associated with pubertal classifications, and twenty-two genes/regions were associated with whether puberty was attained during the trial. Additionally, whole genome sequencing (WGS) data on 33 heifers were aligned to the reference genome (ARS-UCD1.2) to identify variants in FSHR, a gene critical to pubertal attainment. Fisher's exact test determined if FSHR SNPs segregated by pubertal classification. Two FSHR SNPs that were not on the bovine SNP panel were selected for additional genotyping and analysis, and one was associated with pubertal classifications and whether they cycled during the trial. Discussion: In summary, these pubertal classifications are moderately to highly heritable and polygenic. Consequently, genomic tools to inform selection/management of replacement heifers would be useful if informed by SNPs associated with cyclicity and early pubertal attainment.
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Affiliation(s)
- Melanie K. Hess
- Department of Animal Science, University of Nebraska–Lincoln, Lincoln, NE, United States
| | | | | | | | | | | | | | | | | | | | - Andrea S. Cupp
- Department of Animal Science, University of Nebraska–Lincoln, Lincoln, NE, United States
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Bianco B, Loureiro FA, Trevisan CM, Christofolini DM, Laganà AS, Barbosa CP. Implication of FSHB rs10835638 variant in endometriosis in Brazilian women. EINSTEIN-SAO PAULO 2023; 21:eAO0483. [PMID: 37909652 PMCID: PMC10586852 DOI: 10.31744/einstein_journal/2023ao0483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/24/2023] [Accepted: 06/12/2023] [Indexed: 11/03/2023] Open
Abstract
OBJECTIVE The follicle-stimulating hormone subunit beta gene rs10835638 variant (c.-211G>T) may have detrimental effects on fertility and protective effects against endometriosis. A case-control analysis was performed, aiming to investigate the possible relationship between this variant and the development and/or progression of endometriosis. METHODS This study included 326 women with endometriosis and 482 controls without endometriosis, both confirmed by inspection of the pelvic cavity during surgery. Genotyping was performed using a TaqMan real-time polymerase chain reaction assay. Genotype and allele frequencies and genetic models were compared between the groups. RESULTS The genotype and allele frequencies of the rs10835638 variant did not differ between women with and those without endometriosis. Subdividing the endometriosis group into fertile and infertile groups did not result in a significant difference in these frequencies. However, the subgroup with minimal/mild endometriosis had a higher frequency of the GT genotype than the Control Group, regardless of fertility. The T allele was significantly more common in women with minimal/mild endometriosis than in the Control Group in the recessive model. CONCLUSION The T allele is associated with the development of minimal/mild endometriosis in Brazilian women.
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Affiliation(s)
- Bianca Bianco
- Centro Universitário FMABCSanto AndréSPBrazil Centro Universitário FMABC, Santo André, SP, Brazil.
| | - Flávia Altheman Loureiro
- Centro Universitário FMABCSanto AndréSPBrazil Centro Universitário FMABC, Santo André, SP, Brazil.
| | - Camila Martins Trevisan
- Centro Universitário FMABCSanto AndréSPBrazil Centro Universitário FMABC, Santo André, SP, Brazil.
| | | | - Antonio Simone Laganà
- Unit of Gynecologic Oncology, ARNAS “Civico-Di Cristina-Benfratelli”Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical SpecialtiesUniversity of PalermoPalermoItaly Unit of Gynecologic Oncology, ARNAS “Civico-Di Cristina-Benfratelli”, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
| | - Caio Parente Barbosa
- Centro Universitário FMABCSanto AndréSPBrazil Centro Universitário FMABC, Santo André, SP, Brazil.
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Wang X, Zhang Y, Sun HL, Wang LT, Li XF, Wang F, Wang YL, Li QC. Factors Affecting Artificial Insemination Pregnancy Outcome. Int J Gen Med 2021; 14:3961-3969. [PMID: 34349545 PMCID: PMC8326936 DOI: 10.2147/ijgm.s312766] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/25/2021] [Accepted: 07/07/2021] [Indexed: 11/23/2022] Open
Abstract
Objective The aim of the present study was to explore related clinical pregnancy outcome factors in intrauterine insemination (IUI). Materials and Methods The clinical data of 3984 IUI cycles in 1862 couples experiencing infertility who attended the Reproductive Center of Binzhou Medical University Hospital between July 2006 and July 2017 were retrospectively analyzed. Female and male patient age, endometrial thickness (EMT), the post-wash total motile sperm count (PTMC), artificial insemination timing, insemination frequency, and ovarian stimulation protocols were compared between the study’s pregnant group and non-pregnant group in order to explore any correlation. Results There were statistically significant differences in female and male age, EMT, artificial insemination timing, insemination frequency, and ovarian stimulation protocols between the two groups (p < 0.05). The clinical pregnancy rate was significantly higher in ovarian stimulation cycles than in natural cycles (21.2% and 11.6%, respectively; p < 0.01), the clinical pregnancy rate was significantly higher in double IUI than in single IUI (17.8% and 12.1%, respectively; p < 0.01), and EMT was significantly greater in the pregnant group than in the control group (p < 0.05). However, the differences in clinical pregnancy rates among the PTMC groups were not statistically significant (14.8%, 14.4%, 17.3%, and 17.3%, respectively; p > 0.05). Conclusion The results of the present study demonstrate that the clinical IUI pregnancy rate is correlated with the factors of female age, male age, EMT, artificial insemination timing, insemination frequency, and ovarian stimulation protocols; the ovarian stimulation protocol can noticeably improve the patient pregnancy outcome. Furthermore, compared with single IUI, double IUI can significantly increase the clinical pregnancy rate.
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Affiliation(s)
- Xue Wang
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, 256603, People's Republic of China
| | - Yue Zhang
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, 256603, People's Republic of China
| | - Hong-Liang Sun
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, 256603, People's Republic of China
| | - Li-Ting Wang
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, 256603, People's Republic of China
| | - Xue-Feng Li
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, 256603, People's Republic of China
| | - Fei Wang
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, 256603, People's Republic of China
| | - Yan-Lin Wang
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, 256603, People's Republic of China
| | - Qing-Chun Li
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, 256603, People's Republic of China
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Banerjee AA, Joseph S, Mahale SD. From cell surface to signalling and back: the life of the mammalian FSH receptor. FEBS J 2020; 288:2673-2696. [DOI: 10.1111/febs.15649] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/29/2020] [Revised: 11/17/2020] [Accepted: 11/26/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Antara A. Banerjee
- Division of Structural Biology National Institute for Research in Reproductive Health (Indian Council of Medical Research) Parel India
| | - Shaini Joseph
- Genetic Research Center National Institute for Research in Reproductive Health (Indian Council of Medical Research) Parel India
| | - Smita D. Mahale
- Division of Structural Biology National Institute for Research in Reproductive Health (Indian Council of Medical Research) Parel India
- ICMR Biomedical Informatics Centre National Institute for Research in Reproductive Health (Indian Council of Medical Research) Parel India
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Bang AK, Almstrup K, Nordkap L, Priskorn L, Petersen JH, Blomberg Jensen M, Krause M, Holmboe SA, Egeberg Palme DL, Winge SB, Joensen UN, Olesen IA, Hvidman HW, Juul A, Rajpert-De Meyts E, Jørgensen N. FSHB and FSHR gene variants exert mild modulatory effect on reproductive hormone levels and testis size but not on semen quality: A study of 2020 men from the general Danish population. Andrology 2020; 9:618-631. [PMID: 33236519 DOI: 10.1111/andr.12949] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/21/2020] [Revised: 11/01/2020] [Accepted: 11/20/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Spermatogenesis depends on stimulation by follicle-stimulating hormone (FSH) which binds to FSH receptors (FSHR) on testicular Sertoli cells. Three FSH-related single-nucleotide polymorphisms (SNPs), FSHB -211G>T (rs10835638), FSHR -29G>A (rs1394205) and FSHR 2039A>G (rs6166) affect FSH action, and have been suggested to affect testicular function, but the evidence is uncertain. OBJECTIVE To describe the associations between the three SNPs and testicular function in a large and well-characterised cohort of men from the general population. MATERIALS AND METHODS A cross-sectional study of 2020 Danish men unselected regarding testicular function. Outcome variables were semen parameters, reproductive hormones and testis size. Genotyping was done by competitive allele-specific quantitative PCR. Differences in genotype frequencies were tested by chi-square test and associations between genotypes and outcomes were assessed by multivariate linear regressions. RESULTS The SNPs affected serum FSH; carriers of the variant affecting FSH secretion (FSHB -211G>T) had lower FSH levels while carriers of variants affecting receptor expression (FSHR -29G>A) and receptor sensitivity (FSHR 2039A>G) had higher FSH levels. Carriers of FSHB -211G>T had lower calculated free testosterone/LH ratio. Although both FSHB -211G>T and FSHR 2039A>G were associated with smaller testis size, no clear association was detected in relation to any semen parameters, except a lower total number of morphologically normal spermatozoa in the heterozygous carriers of the FSHB -211G>T DISCUSSION AND CONCLUSION: The studied polymorphisms have only minor modulating influence on testis size and function in healthy men. We detected subtle effects of the three SNPs on FSH levels, but also effects of FSHB -211G>T on calculated free testosterone/LH ratio, compatible with altered Leydig cell function. Thus, the role of these FSH-related polymorphisms is complex and modest in men with normal testicular function, but the possible importance of FSH polymorphisms in men with impaired testicular function should be evaluated in future studies in more detail.
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Affiliation(s)
- Anne Kirstine Bang
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Kristian Almstrup
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Loa Nordkap
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Laerke Priskorn
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen Holm Petersen
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.,Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
| | - Martin Blomberg Jensen
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Marianna Krause
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Stine Agergaard Holmboe
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Dorte Louise Egeberg Palme
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Sofia Boeg Winge
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ulla Nordström Joensen
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.,Department of Urology, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Inge Ahlmann Olesen
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Anders Juul
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ewa Rajpert-De Meyts
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Niels Jørgensen
- Department of Growth and Reproduction and International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Bahrehbar K, Rezazadeh Valojerdi M, Esfandiari F, Fathi R, Hassani SN, Baharvand H. Human embryonic stem cell-derived mesenchymal stem cells improved premature ovarian failure. World J Stem Cells 2020; 12:857-878. [PMID: 32952863 PMCID: PMC7477659 DOI: 10.4252/wjsc.v12.i8.857] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/22/2020] [Revised: 06/01/2020] [Accepted: 07/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. According to previous reports, various tissue-specific stem cells can restore ovarian function and folliculogenesis in mice with chemotherapy-induced POF. Human embryonic stem cells (ES) provide an alternative source for mesenchymal stem cells (MSCs) because of their similarities in phenotype and immunomodulatory and anti-inflammatory characteristics. Embryonic stem cell-derived mesenchymal stem cells (ES-MSCs) are attractive candidates for regenerative medicine because of their high proliferation and lack of barriers for harvesting tissue-specific MSCs. However, possible therapeutic effects and underlying mechanisms of transplanted ES-MSCs on cyclophosphamide and busulfan-induced mouse ovarian damage have not been evaluated. AIM To evaluate ES-MSCs vs bone marrow-derived mesenchymal stem cells (BM-MSCs) in restoring ovarian function in a mouse model of chemotherapy-induced premature ovarian failure. METHODS Female mice received intraperitoneal injections of different doses of cyclophosphamide and busulfan to induce POF. Either human ES-MSCs or BM-MSCs were transplanted into these mice. Ten days after the mice were injected with cyclophosphamide and busulfan and 4 wk after transplantation of the ES-MSCs and/or BM-MSCs, we evaluated body weight, estrous cyclicity, follicle-stimulating hormone and estradiol hormone concentrations and follicle count were used to evaluate the POF model and cell transplantation. Moreover, terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling, real-time PCR, Western blot analysis and immunohistochemistry and mating was used to evaluate cell transplantation. Enzyme-linked immunosorbent assay was used to analyze vascular endothelial growth factor, insulin-like growth factor 2 and hepatocyte growth factor levels in ES-MSC condition medium in order to investigate the mechanisms that underlie their function. RESULTS The human ES-MSCs significantly restored hormone secretion, survival rate and reproductive function in POF mice, which was similar to the results obtained with BM-MSCs. Gene expression analysis and the terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling assay results indicated that the ES-MSCs and/or BM-MSCs reduced apoptosis in the follicles. Notably, the transplanted mice generated new offspring. The results of different analyses showed increases in antiapoptotic and trophic proteins and genes. CONCLUSION These results suggested that transplantation of human ES-MSCs were similar to BM-MSCs in that they could restore the structure of the injured ovarian tissue and its function in chemotherapy-induced damaged POF mice and rescue fertility. The possible mechanisms of human ES-MSC were related to promotion of follicular development, ovarian secretion, fertility via a paracrine effect and ovarian cell survival.
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Affiliation(s)
- Khadijeh Bahrehbar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran 1665659911, Iran
| | - Mojtaba Rezazadeh Valojerdi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Tehran 1665659911, Iran
- Department of Anatomy, Faculty of Medical Science, Tarbiat Modares University, Tehran 1665659911, Iran
| | - Fereshteh Esfandiari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
| | - Rouhollah Fathi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Tehran 1665659911, Iran
| | - Seyedeh-Nafiseh Hassani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran 1665659911, Iran.
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Yan J, Tian Y, Gao X, Cui L, Ning Y, Cao Y, Chen Y, Peng F, You L, Liu F, Zhao H. A genome-wide association study identifies FSHR rs2300441 associated with follicle-stimulating hormone levels. Clin Genet 2020; 97:869-877. [PMID: 32185793 DOI: 10.1111/cge.13741] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/10/2019] [Revised: 02/27/2020] [Accepted: 03/04/2020] [Indexed: 12/21/2022]
Abstract
Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) play critical roles in female reproduction, while the underlying genetic basis is poorly understood. Genome-wide association studies (GWASs) of FSH and LH levels were conducted in 2590 Chinese females including 1882 polycystic ovary syndrome (PCOS) cases and 708 controls. GWAS for FSH level identified multiple variants at FSHR showing genome-wide significance with the top variant (rs2300441) located in the intron of FSHR. The A allele of rs2300441 led to a reduced level of FSH in the PCOS group (β = -.43, P = 6.70 × 10-14 ) as well as in the control group (β = -.35, P = 6.52 × 10-4 ). In the combined sample, this association was enhanced after adjusting for the PCOS status (before: β = -.38, P = 1.77 × 10-13 ; after: β = -.42, P = 3.33 × 10-16 ), suggesting the genetic effect is independent of the PCOS status. The rs2300441 explained sevenfold higher proportion of the FSH variance than the total variance explained by the two previously reported FSHR missense variants (rs2300441 R2 = 1.40% vs rs6166 R2 = 0.17%, rs6165 R2 = 0.03%). GWAS for LH did not identify any genome-wide significant associations. In conclusion, we identified genome-wide significant association between variants in FSHR and circulating FSH first, with the top associated variant rs2300441 might be a primary contributor at the population level.
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Affiliation(s)
- Jinting Yan
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Ye Tian
- Center for Reproductive Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China.,The Key Laboratory for Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan, China.,Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Xingjian Gao
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Linlin Cui
- Center for Reproductive Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China.,The Key Laboratory for Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan, China
| | - Yunna Ning
- Center for Reproductive Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China.,The Key Laboratory for Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan, China
| | - Yongzhi Cao
- Center for Reproductive Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China.,The Key Laboratory for Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan, China
| | - Yan Chen
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Fuduan Peng
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Li You
- Center for Reproductive Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China.,The Key Laboratory for Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan, China
| | - Fan Liu
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.,Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Han Zhao
- Center for Reproductive Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China.,The Key Laboratory for Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan, China
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Rull K, Grigorova M, Ehrenberg A, Vaas P, Sekavin A, Nõmmemees D, Adler M, Hanson E, Juhanson P, Laan M. FSHB -211 G>T is a major genetic modulator of reproductive physiology and health in childbearing age women. Hum Reprod 2019; 33:954-966. [PMID: 29617818 DOI: 10.1093/humrep/dey057] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/03/2017] [Accepted: 03/05/2018] [Indexed: 11/13/2022] Open
Abstract
STUDY QUESTION Are the genetic variants FSHB -211 G>T (rs10835638), FSHR c.2039 A>G (Asn680Ser, rs6166) and FSHR -29 G>A (rs1394205) associated with serum FSH, LH and anti-Müllerian hormone (AMH) levels in reproductive age women, their menstrual cycle parameters and risk of infertility? SUMMARY ANSWER Only the FSHB -211 G>T variant was a major genetic determinant of serum gonadotropin levels in both, eumenorrheic healthy women and female infertility patients, and the T-allele carrier status was enriched among idiopathic infertility cases. WHAT IS KNOWN ALREADY There are accumulating data on common genetic variants modulating reproductive parameters and fertility potential. FSHB -211 G>T represents the strongest acknowledged genetic factor contributing to male circulating gonadotropins levels. Respective data in women are limited and the two previously published studies have reached conflicting results. In addition, previous studies have consistently associated FSHR c.2039 A>G (but not FSHR -29 G>A) with female serum FSH level. STUDY DESIGN, SIZE, DURATION The study aimed to test robust and clinically meaningful genetic effects (if present) of the FSHB -211 G>T, FSHR c.2039 A>G and FSHR -29 G>A variants on female basal FSH, LH and AMH levels, and linked reproductive parameters. Genetic association testing was performed in two independent and clinically different study groups (i) eumenorrheic healthy women without known fertility problems (n = 169; 27.6 ± 6.1 years) and (ii) female partners of infertile couples (n = 186; 32.4 ± 4.7 years). The study groups were compared for allelic and genotypic distributions of the analysed variants. PARTICIPANTS/MATERIALS, SETTING, METHODS All participants were recruited during the HAPPY PREGNANCY study (2013-2015) at the Women's Clinic, Tartu University Hospital, Estonia. Serum FSH, LH and AMH were measured in the follicular phase (Days 2-6) of the menstrual cycle. All three single nucleotide polymorphisms (SNPs) were genotyped by PCR and Taqman allelic discrimination assay. The effect of the analysed variants on hormonal measurements and menstrual cycle data was assessed using linear regression under additive and recessive models adjusted by age, BMI and smoking status. Results of the two subgroups were combined in a meta-analysis applying the fixed effects model. Restricted maximum likelihood analysis was applied to estimate the proportion of total phenotypic variance of analysed reproductive parameters, explainable by the tested genetic variants. In case-control analysis, genetic association with infertility status was tested using Fisher's exact test and logistic regression adjusted by age, BMI and smoking status. MAIN RESULTS AND THE ROLE OF CHANCE In both study groups, T-allele of the FSHB -211 G>T was associated with significantly higher serum levels of FSH and LH. Results of the meta-analysis (additive genetic model) remained significant after Bonferroni correction for multiple testing: FSH, T-allele effect 0.80 IU/L, P = 1.2 × 10-3; LH, 1.58 IU/L, P = 1.8×10-8. A more pronounced effect of T-allele of the FSHB -211 G>T on circulating LH was identified as a driving factor to increased LH/FSH ratio (meta-analysis, P = 4.7 × 10-3). In healthy women, the FSHB -211 G>T variant was estimated to explain 3.5 and 7.1% of the total variance of the measured serum FSH and LH levels, respectively. The corresponding numbers for the infertility patients were 1.6 and 10.5%. Women with idiopathic infertility compared to controls exhibited a doubled T-allele frequency (23.6 versus 12.4%; P = 8.9 × 10-3) and a >3-fold excess of TT homozygotes (5.6 versus 1.8%; P = 3.5 × 10-2). The only association of the FSHR c.2039 A>G was detected with serum FSH levels in eumenorrheic healthy women, explaining 3.9% of the total parameter variance (G-allele effect 0.56 IU/L, P = 4.6 × 10-3). In the study group of healthy reproductive age women, the highest serum FSH levels were detected among the FSHB -211 T-allele carriers with the FSHR c.2039 GG-genotype (median 7.7 IU/L). In contrast, the lowest hormone concentrations were measured for the women carrying the combination of the FSHB -211 GG- and the FSHR c.2039 AA-homozygosity (median 5.8 IU/L, P = 9.6 × 10-3). None of the analysed reproductive parameters was associated with the FSHR -29 G>A variant. In our study groups, the tested polymorphisms did not reach significant associations with serum AMH measurements, menstrual cycle length or age at menarche. LIMITATIONS, REASONS FOR CAUTION Small sample size and the design involving two clinical groups with different reproductive histories may have limited the capacity to replicate the associations with the age at menarche and length of menstrual cycle, initially reported in large genome-wide association studies. Small sample size may have also affected the accuracy in estimating the contribution of the tested variants to the total phenotypic variance of measured gonadotropin concentrations. The group of eumenorrheic healthy women had its limitations as a control to estimate the true effect of analysed genetic variants on individual's fertility potential as the recruitment strategy had been targeted mostly towards younger women, who may not yet have planned to conceive a child by this age. WIDER IMPLICATIONS OF THE FINDINGS We propose that like in men, also in women the FSHB -211 G>T represents a key genetic modulator of circulating gonadotropin, leading to various possible downstream effects on reproductive physiology. This claim is strongly supported by the reports of genome-wide association studies on various female reproductive traits and diseases. In perspective, FSHB -211 G>T may have a diagnostic value in fertility clinics to detect female patients with genetically inherited elevated basal FSH and LH levels. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by Estonian Science Foundation Grant (ETF9030 for M.L.); Institutional Research Grant (IUT34-12 for M.L.) and European Union through the European Regional Development Fund (project HAPPY PREGNANCY, 3.2.0701.12-0047; for M.L. and K.R.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the article. We have no competing interests to declare. TRAIL REGISTRATION NUMBER Not applicable.
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Affiliation(s)
- Kristiina Rull
- Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila St. 19, Tartu 50411, Estonia.,Department of Obstetrics and Gynaecology, University of Tartu, L. Puusepa St. 8, Tartu 51014, Estonia.,Women's Clinic of Tartu University Hospital, L. Puusepa St. 8, Tartu 51014, Estonia
| | - Marina Grigorova
- Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila St. 19, Tartu 50411, Estonia
| | - Aivar Ehrenberg
- Department of Obstetrics and Gynaecology, University of Tartu, L. Puusepa St. 8, Tartu 51014, Estonia.,Women's Clinic of Tartu University Hospital, L. Puusepa St. 8, Tartu 51014, Estonia
| | - Pille Vaas
- Department of Obstetrics and Gynaecology, University of Tartu, L. Puusepa St. 8, Tartu 51014, Estonia.,Women's Clinic of Tartu University Hospital, L. Puusepa St. 8, Tartu 51014, Estonia
| | - Aire Sekavin
- Department of Obstetrics and Gynaecology, University of Tartu, L. Puusepa St. 8, Tartu 51014, Estonia
| | - Diana Nõmmemees
- Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila St. 19, Tartu 50411, Estonia
| | - Mart Adler
- Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila St. 19, Tartu 50411, Estonia
| | - Ele Hanson
- Department of Obstetrics and Gynaecology, University of Tartu, L. Puusepa St. 8, Tartu 51014, Estonia.,Women's Clinic of Tartu University Hospital, L. Puusepa St. 8, Tartu 51014, Estonia
| | - Peeter Juhanson
- Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila St. 19, Tartu 50411, Estonia
| | - Maris Laan
- Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila St. 19, Tartu 50411, Estonia
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9
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Trevisan CM, de Oliveira R, Christofolini DM, Barbosa CP, Bianco B. Effects of a Polymorphism in the Promoter Region of the Follicle-Stimulating Hormone Subunit Beta (FSHB) Gene on Female Reproductive Outcomes. Genet Test Mol Biomarkers 2018; 23:39-44. [PMID: 30585745 DOI: 10.1089/gtmb.2018.0182] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Follicle-stimulating hormone (FSH) is essential to the hypothalamic-pituitary-gonadal axis, playing a key role in human reproduction. It is a heterodimer comprised of a hormone-specific β-chain (FSH-β) that is associated with an α-chain. It exerts its biological activities by binding to the FSH receptor (FSHR). The β-subunit, which is encoded by the FSHB gene, is responsible for ensuring binding specificity to the FSHR. There is a promoter polymorphism in this gene, c.-211G>T (rs10835638), upstream of the transcription start site; and in vitro studies have reported that the T allele decreases FSHB transcription in gonadotrophic cells. AIMS Investigate the possible effects of the FSHB c.-211G/T polymorphism on hormonal profile and in in vitro fertilization (IVF)/intracytoplasmic sperm injection outcomes in normoovulatory Brazilian women. METHODS A cross-sectional study of 140 women (median age = 33 years [CI: 32-34]) with infertility mainly caused by male (n = 85) or tuboperitoneal (n = 55) factors. In this study we evaluated FSH, estradiol, luteinizing hormone (LH), progesterone, prolactin and anti-Mullerian hormone levels, and antral follicle counting (AFC). Genotyping was performed using the TaqMan real-time polymerase chain reaction methodology. RESULTS The wild-type allele G was found in 86.4% and the polymorphic allele T in 13.6% of the women respectively. The TT genotype was not found in any women. Women carrying the GT genotype had a poorer response more frequently to controlled ovarian hyperstimulation when compared to individuals with the GG genotype (47.4% vs. 26.5%, p = 0.010), higher LH levels (3.1 IU/mL vs. 2.4 IU/mL, p = <0.001), lower AFC (8.0 vs. 10.0, p = 0.03), oocytes retrieved (3.0 vs. 5.0, p = 0.03), MII (3.0 vs. 4.0, p = 0.02), and embryos (2.0 vs. 3.0, p = 0.02). Despite these findings, no difference was observed in pregnancy rate. CONCLUSION Our findings suggest that the FSHB c.-211G/T polymorphism may modestly alter some aspects of the female reproductive system, but they are not associated with significantly different IVF outcomes.
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Affiliation(s)
- Camila Martins Trevisan
- Human Reproduction and Genetics, Department of Collective Health, Faculdade de Medicina do ABC , Santo André/SP, Brazil
| | - Renato de Oliveira
- Human Reproduction and Genetics, Department of Collective Health, Faculdade de Medicina do ABC , Santo André/SP, Brazil
| | - Denise Maria Christofolini
- Human Reproduction and Genetics, Department of Collective Health, Faculdade de Medicina do ABC , Santo André/SP, Brazil
| | - Caio Parente Barbosa
- Human Reproduction and Genetics, Department of Collective Health, Faculdade de Medicina do ABC , Santo André/SP, Brazil
| | - Bianca Bianco
- Human Reproduction and Genetics, Department of Collective Health, Faculdade de Medicina do ABC , Santo André/SP, Brazil
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10
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Busch AS, Hagen CP, Assens M, Main KM, Almstrup K, Juul A. Differential Impact of Genetic Loci on Age at Thelarche and Menarche in Healthy Girls. J Clin Endocrinol Metab 2018; 103:228-234. [PMID: 29077908 DOI: 10.1210/jc.2017-01860] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/21/2017] [Accepted: 10/20/2017] [Indexed: 02/04/2023]
Abstract
CONTEXT Recent genetic studies have identified genetic variants associated with age at pubertal onset. Whereas genome-wide association studies reported associations of several hundred genetic variants with timing of self-reported age at menarche, a recent clinical study focused on genetic variation affecting follicle-stimulating hormone action and clinically determined age at thelarche. The observations appear to be incongruent, as effect sizes varied substantially among the studies. Alternatively, this may point to a differential impact of specific genetic loci on distinct pubertal events. OBJECTIVE To investigate whether top-candidate genetic variants exhibit a different impact on timing of thelarche vs menarche, respectively. DESIGN Cross-sectional and longitudinal study of healthy girls. SETTING Population-based study in the Copenhagen area. PATIENTS OR OTHER PARTICIPANTS Girls (1478) were followed through puberty and genotyped for FSHB c.-211G>T (rs10835638), FSHR c.-29G>A (rs1394205), FSHR c.2039A>G (rs6116), LIN28B (rs7759938), INHA (rs4141153), MKRN3 (rs12148769), TMEM38B (rs10453225), and ZNF483 (rs10980921). MAIN OUTCOME MEASURES Clinical pubertal staging and anthropometric data. RESULTS We observed an association of LIN28B (rs7759938) with age at thelarche (P < 0.001, effect size: 0.27 year, 95% confidence interval: 0.12 to 0.42) and age at menarche (P = 0.005, 0.17 year, 0.05 to 0.29). FSHB c.-211G>T (rs10835638) and FSHR c.-29G>A (rs1394205) minor allele count was associated with age at thelarche (P = 0.004, 0.19 year, 0.06 to 0.31) but not with age at menarche (P = 0.97; all adjusted for body mass index z scores). CONCLUSION Our results indicate a differential impact of specific genetic loci on age at thelarche and menarche in healthy girls.
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Affiliation(s)
- Alexander S Busch
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Casper P Hagen
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Maria Assens
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Katharina M Main
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Kristian Almstrup
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Anders Juul
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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11
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Bang AK, Busch AS, Almstrup K, Gromoll J, Kliesch S, Rajpert-De Meyts E, Skakkebaek NE, Juul A, Tüttelmann F, Jørgensen N. Is the FSHR
2039A>G variant associated with susceptibility to testicular germ cell cancer? Andrology 2017; 6:176-183. [DOI: 10.1111/andr.12440] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/06/2017] [Revised: 09/26/2017] [Accepted: 10/02/2017] [Indexed: 12/12/2022]
Affiliation(s)
- A. K. Bang
- Department of Growth and Reproduction; Rigshospitalet; University of Copenhagen; Copenhagen Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC); Rigshospitalet Denmark
| | - A. S. Busch
- Department of Growth and Reproduction; Rigshospitalet; University of Copenhagen; Copenhagen Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC); Rigshospitalet Denmark
- Centre of Reproductive Medicine and Andrology; Institute of Reproductive and Regenerative Biology; University of Münster; Münster Germany
| | - K. Almstrup
- Department of Growth and Reproduction; Rigshospitalet; University of Copenhagen; Copenhagen Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC); Rigshospitalet Denmark
| | - J. Gromoll
- Centre of Reproductive Medicine and Andrology; Institute of Reproductive and Regenerative Biology; University of Münster; Münster Germany
| | - S. Kliesch
- Centre of Reproductive Medicine and Andrology; Department of Clinical and Surgical Andrology; University of Münster; Münster Germany
| | - E. Rajpert-De Meyts
- Department of Growth and Reproduction; Rigshospitalet; University of Copenhagen; Copenhagen Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC); Rigshospitalet Denmark
| | - N. E. Skakkebaek
- Department of Growth and Reproduction; Rigshospitalet; University of Copenhagen; Copenhagen Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC); Rigshospitalet Denmark
| | - A. Juul
- Department of Growth and Reproduction; Rigshospitalet; University of Copenhagen; Copenhagen Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC); Rigshospitalet Denmark
| | - F. Tüttelmann
- Institute of Human Genetics; University of Münster; Münster Germany
| | - N. Jørgensen
- Department of Growth and Reproduction; Rigshospitalet; University of Copenhagen; Copenhagen Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC); Rigshospitalet Denmark
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12
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Ding C, Li H, Wang Y, Wang F, Wu H, Chen R, Lv J, Wang W, Huang B. Different therapeutic effects of cells derived from human amniotic membrane on premature ovarian aging depend on distinct cellular biological characteristics. Stem Cell Res Ther 2017; 8:173. [PMID: 28750654 PMCID: PMC5530953 DOI: 10.1186/s13287-017-0613-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/23/2017] [Revised: 06/14/2017] [Accepted: 06/16/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Many reports have shown that various kinds of stem cells have the ability to recover premature ovarian aging (POA) function. Transplantation of human amniotic epithelial cells (hAECs) improves ovarian function damaged by chemotherapy in a mice model. Understanding of how to evaluate the distinct effects of adult stem cells in curing POA and how to choose stem cells in clinical application is lacking. METHODS To build a different degrees of POA model, mice were administered different doses of cyclophosphamide: light dose (70 mg/kg, 2 weeks), medium dose (70 mg/kg, 1 week; 120 mg/kg, 1 week), and high dose (120 mg/kg, 2 weeks). Enzyme-linked immunosorbent assay detected serum levels of sex hormones, and hematoxylin and eosin staining allowed follicle counting and showed the ovarian tissue structure. DiIC18(5)-DS was employed to label human amniotic mesenchymal stem cells (hAMSCs) and hAECs for detecting the cellular retention time in ovaries by a live imaging system. Proliferation of human ovarian granule cells (ki67, AMH, FSHR, FOXL2, and CYP19A1) and immunological rejection of human peripheral blood mononuclear cells (CD4, CD11b, CD19, and CD56) were measured by flow cytometry (fluorescence-activated cell sorting (FACS)). Distinction of cellular biological characteristics between hAECs and hAMSCs was evaluated, such as collagen secretory level (collagen I, II, III, IV, and VI), telomerase activity, pluripotent markers tested by western blot, expression level of immune molecules (HLA-ABC and HLA-DR) analyzed by FACS, and cytokines (growth factors, chemotactic factors, apoptosis factors, and inflammatory factors) measured by a protein antibody array methodology. RESULTS After hAMSCs and hAECs were transplanted into a different degrees of POA model, hAMSCs exerted better therapeutic activity on mouse ovarian function in the high-dose administration group, promoting the proliferation rate of ovarian granular cells from premature ovarian failure patients, but also provoking immune rejection. Meanwhile, our results showed that the biological characteristics of hAMSCs were superior to hAECs, but not to expression of immune molecules. CONCLUSIONS These results suggest that hAMSCs are a more effective cell type to improve ovarian function than hAECs. Meanwhile, this distinct effect is attributable to cellular biological characteristics of hAMSCs (telomerase activity, expression level of pluripotent markers, cytokine and collagen secretion) that are superior to hAECs, except for immunological rejection. Sufficient consideration of cell properties is warranted to move forward to more effective clinical therapy.
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Affiliation(s)
- Chenyue Ding
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215002, China
| | - Hong Li
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215002, China
| | - Yun Wang
- Department of Obstetrics and Gynecology, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215002, China
| | - Fuxin Wang
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215002, China
| | - Huihua Wu
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215002, China
| | - Rulei Chen
- Department of Pathology, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215002, China
| | - Jinghuan Lv
- Department of Pathology, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215002, China
| | - Wei Wang
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215002, China
| | - Boxian Huang
- Center of Reproduction and Genetics, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, 215002, China. .,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 210029, China.
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13
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Busch AS, Hagen CP, Main KM, Pereira A, Corvalan C, Almstrup K, Mericq V, Juul A. Genetic Variation of Follicle-Stimulating Hormone Action Is Associated With Age at Testicular Growth in Boys. J Clin Endocrinol Metab 2017; 102:1740-1749. [PMID: 28323923 DOI: 10.1210/jc.2016-4013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/22/2016] [Accepted: 02/22/2017] [Indexed: 02/07/2023]
Abstract
CONTEXT Although genetic factors play a pivotal role in male pubertal timing, genome-wide association studies have identified only a few loci. Genetic variation of follicle-stimulating hormone (FSH) action affects adult reproductive parameters and female pubertal timing. OBJECTIVE To investigate whether genetic variation affecting FSH action is associated with onset of puberty in boys. DESIGN Cross-sectional and longitudinal study of two cohorts of healthy boys. SETTING This was a population-based study. PATIENTS OR OTHER PARTICIPANTS Danish (n = 1130) and Chilean (n = 424) boys were followed through puberty and genotyped for FSHB c.-211G>T, FSHR c.-29A>G, and FSHR c.2039G>A. MAIN OUTCOME MEASURES Clinical pubertal staging including orchidometry, anthropometry, and serum gonadotropin levels. RESULTS Although the cohorts differed markedly (e.g., body composition and genotype frequencies), genetic variation affecting FSH production (FSHB c.-211G>T) was associated with age at pubertal onset, as assessed by testicular enlargement, in both cohorts. The effect appeared further modified by coexistence of genetic variation affecting FSH sensitivity (FSHR c.-29G>A): After correcting for body mass index (BMI), boys with a ligand-receptor variant combination resulting in weak FSH action (i.e., FSHB c.-211GT/TT and FSHR c.-29AA) entered puberty 0.64 years [95% confidence interval (CI), 0.12 to 1.17 years; Denmark] and 0.94 years (95% CI, 0.00 to 1.88 years; Chile) later than boys with the most effective FSH action. Effects explained 1.7% (Denmark) and 1.5% (Chile) of the variance. In addition, BMI z score was negatively associated with pubertal timing (β = -0.35 years in both cohorts), explaining 17.2% (Denmark) and 7.2% (Chile) of the variance. CONCLUSION In two ethnically distinct populations, we independently identified an association of two genetic loci with male pubertal timing.
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Affiliation(s)
- Alexander S Busch
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Casper P Hagen
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Katharina M Main
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Anita Pereira
- Institute of Nutrition and Food Technology, University of Chile, Casilla 226-3, Santiago 8360160, Chile
| | - Camila Corvalan
- Institute of Nutrition and Food Technology, University of Chile, Casilla 226-3, Santiago 8360160, Chile
| | - Kristian Almstrup
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Veronica Mericq
- Institute of Maternal and Child Research, Faculty of Medicine, University of Chile, Casilla 226-3, Santiago 8360160, Chile
| | - Anders Juul
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
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14
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Genetics of gonadotropins and their receptors as markers of ovarian reserve and response in controlled ovarian stimulation. Best Pract Res Clin Obstet Gynaecol 2017; 44:15-25. [PMID: 28506471 DOI: 10.1016/j.bpobgyn.2017.04.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/14/2017] [Revised: 02/03/2017] [Accepted: 04/01/2017] [Indexed: 01/11/2023]
Abstract
Several controlled ovarian stimulation (COS) protocols have been developed to increase the yield of mature oocytes retrieved in assisted reproductive techniques (ARTs). The ovarian reserve (OR) influences the COS response, and it represents the main parameter that helps clinicians in refining clinical treatments in the perspective of a "personalized" ART. This approach is even more needed in particular conditions such as poor OR or polycystic ovary syndrome. Follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin are currently used in COS at different combinations and with different efficacies, even if the best approach definition is controversial. Differences in individual-specific ovarian response to gonadotropin stimulation can be due to alterations of genes encoding for hormones or their receptors. In particular, FSHB c.-211G>T, FSHR p.Asn680Ser, and c.-29G>A SNP allelic combinations may be used as OR and COS response markers. The purpose of this review is to highlight the evidence-based relevance of mutations and polymorphisms in gonadotropins and their receptor genes as predictive markers of OR and COS response to achieve fine-tuned therapeutic regimens.
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15
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Lindhardt Johansen M, Hagen CP, Mieritz MG, Wolthers OD, Heuck C, Petersen JH, Juul A. Pubertal Progression and Reproductive Hormones in Healthy Girls With Transient Thelarche. J Clin Endocrinol Metab 2017; 102:1001-1008. [PMID: 28009526 DOI: 10.1210/jc.2016-2871] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/01/2016] [Accepted: 12/22/2016] [Indexed: 12/15/2022]
Abstract
CONTEXT Detailed evaluation of pubertal progression in girls from longitudinal studies is sparse, and the phenomenon of transient thelarche (TT), defined as the appearance, regression, and subsequent reappearance of breast buds, in healthy girls remains undescribed. OBJECTIVE To describe TT in terms of pubertal progression, growth, genotypes, and reproductive hormones and to apply new puberty nomograms for breast stages, pubic hair, and menarche. DESIGN A prospective, longitudinal population-based study. PATIENTS OR OTHER PARTICIPANTS Ninety-eight healthy Danish schoolchildren (Caucasian girls) followed longitudinally as part of the COPENHAGEN Puberty Study were included in the evaluation of TT. A total of 1466 girls from 2 cross-sectional studies were included in the creation of the puberty nomograms. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Pubertal progression, specifically thelarche, reproductive hormones, genotype, and growth. RESULTS Twelve of 98 (12%) girls experienced TT. A larger proportion of girls with TT entered puberty by the pubarche pathway (50%) compared with girls with normal progression (15.4%), P = 0.014. Girls with TT progressed through puberty normally when evaluated using puberty nomograms. Reproductive hormones and growth velocity were lower at the first (transient) thelarche than the second (permanent) thelarche. CONCLUSION TT is a frequent phenomenon that appears to be a peripheral occurrence independent of central puberty. It does not appear to affect subsequent pubertal progression as evaluated by our new puberty nomograms.
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Affiliation(s)
- Marie Lindhardt Johansen
- Department of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - Casper P Hagen
- Department of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - Mikkel G Mieritz
- Department of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - Ole D Wolthers
- Asthma and Allergy Clinic, Children's Clinic Randers, DK-8900 Randers, Denmark
| | - Carsten Heuck
- Department of Pediatrics, Aalborg University Hospital, DK-9100 Aalborg, Denmark; and
| | - Jørgen Holm Petersen
- Department of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - Anders Juul
- Department of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, University of Copenhagen, DK-2100 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
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Zhao JV, Schooling CM. Endogenous androgen exposures and ischemic heart disease, a separate sample Mendelian randomization study. Int J Cardiol 2016; 222:940-945. [PMID: 27526363 DOI: 10.1016/j.ijcard.2016.07.174] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/03/2016] [Accepted: 07/27/2016] [Indexed: 12/21/2022]
Abstract
BACKGROUND Evolutionary biology suggests growth and reproduction trade-off against longevity. Correspondingly estrogen supplementation failed to increase lifespan. Testosterone supplementation is widely used by older men, although regulators have warned of its cardiovascular risk. No large trial of testosterone exists. We examined how genetic determinants of up-regulation (follicle-stimulating hormone (FSH)) and down-regulation (anti-Müllerian hormone (AMH) and testicular dysgenesis syndrome (TDS)) of mainly the male reproductive system are associated with ischemic heart disease (IHD). METHODS Separate sample instrumental variable analysis with genetic instruments, i.e., Mendelian randomization, was used to obtain unconfounded estimates using large case-control studies of coronary artery disease/myocardial infarction (CAD/MI) with extensive genotyping, i.e., CARDIoGRAMplusC4D (64,374 CAD/MI cases, 130,681controls), or CARDIoGRAMplusC4D 1000 Genomes (60,801 cases, 123,504 controls). RESULTS Genetically predicted FSH was positively associated with CAD/MI (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.03 to 1.13 per mIU/mL FSH). Genetically predicted AMH and TDS were inversely associated with CAD/MI (OR 0.93, 95% CI 0.87 to 0.998 per ng/mL log AMH and OR 0.89, 95% CI 0.81 to 0.98 per log OR higher risk of TDS). CONCLUSIONS As expected from evolutionary biology, genetically predicted FSH, related to higher androgens in men and women, was positively associated with IHD, while genetically predicted AMH and TDS, related to lower androgens in men, were inversely associated with IHD. Androgens might be a modifiable causal factor underlying men's greater vulnerability to IHD, with corresponding implications for use of testosterone supplementation as well as for prevention and treatment of IHD.
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Affiliation(s)
- Jie V Zhao
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - C Mary Schooling
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; City University of New York, School of Public Health and Health Policy, New York, NY, USA.
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