Volume 19, Issue 6 (June 2021)                   IJRM 2021, 19(6): 493-504 | Back to browse issues page


XML Persian Abstract Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Asadi A, Ghahremani R, Abdolmaleki A, Rajaei F. Role of sperm apoptosis and oxidative stress in male infertility: A narrative review. IJRM 2021; 19 (6) :493-504
URL: http://ijrm.ir/article-1-1787-en.html
1- Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran.
2- Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran. BioScience and Biotechnology Research Center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran. , Abdolmalekiarash1364@gmail.com
3- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.
Abstract:   (1732 Views)
Activation of caspase, externalization of phosphatidyl serine, change in the mitochondrial membrane potential, and DNA fragmentation are apoptosis markers found in human ejaculated spermatozoa. Also, reactive oxygen species (ROS) play a vital role in the different types of male infertility. In this review, data sources including Google Scholar, Scopus, PubMed, and Science Direct were searched for publications with no particular time restriction to get a holistic and comprehensive view of the research. Apoptosis regulates the male germ cells, correct function and development from the early embryonic stages of gonadal differentiation to fertilization. In addition to maintaining a reasonable ratio between the Sertoli and germ cells, apoptosis is one of the well-known quality control mechanisms in the testis. Also, high ROS levels cause a heightened and dysregulated apoptotic response. Apoptosis is one of the well-known mechanisms of quality control in the testis. Nevertheless, increased apoptosis may have adverse effects on sperm production. Recent studies have shown that ROS and the consequent oxidative stress play a crucial role in apoptosis. This review aims to assimilate and summarize recent findings on the apoptosis in male reproduction and fertility. Also, this review discusses the update on the role of ROS in normal sperm function to guide future research in this area.
 
Full-Text [PDF 1214 kb]   (1025 Downloads) |   |   Full-Text (HTML)  (365 Views)  
Type of Study: Review Article | Subject: Reproductive Biology

References
1. Latchoumycandane C, Vaithinathan S, D'Cruz S, Mathur PP. Apoptosis and male infertility. In: Parekattil SJ, Esteves SC, Agarwal A. Male infertility. Switzeland: Springer; 2020. 479-486. [DOI:10.1007/978-3-030-32300-4_37]
2. Bejarano I, Rodríguez AB, Pariente JA. Apoptosis is a demanding selective tool during the development of fetal male germ cells. Front Cell Dev Biol 2018; 6: 65. 1-7. [DOI:10.3389/fcell.2018.00065] [PMID] [PMCID]
3. MacLeod J. The role of oxygen in the metabolism and motility of human spermatozoa. Am J Physiol-Leg Content 1943; 138: 512-518. [DOI:10.1152/ajplegacy.1943.138.3.512]
4. Bisht Sh, Faiq M, Tolahunase M, Dada R. Oxidative stress and male infertility. Nat Rev Urol 2017; 14: 470-485. [DOI:10.1038/nrurol.2017.69] [PMID]
5. Makker K, Agarwal A, Sharma R. Oxidative stress & male infertility. Indian J Med Res 2009; 129: 357-367.
6. Sharma R, Agarwal A, Rohra VK, Assidi M, Abu-Elmagd M, Turki RF. Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. Reprod Biol Endocrinol 2015; 13: 35. 1-20. [DOI:10.1186/s12958-015-0028-x] [PMID] [PMCID]
7. World Health Organization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. UK: Cambridge University press; 1999.
8. Brahem S, Mehdi M, Elghezal H, Saad A. The effects of male aging on semen quality, sperm DNA fragmentation and chromosomal abnormalities in an infertile population. J Assist Reprod Genet 2011; 28: 425-432. [DOI:10.1007/s10815-011-9537-5] [PMID] [PMCID]
9. Kutluyer F, Çakir Sahilli Y, Kocabaş M, Aksu Ö. Sperm quality and oxidative stress in chub Squalius orientalis and Padanian barbel Barbus plebejus (Teleostei: Cyprinidae) after in vitro exposure to low doses of bisphenol A. Drug Chem Toxicol 2020; 7: 1-6. [DOI:10.1080/01480545.2020.1726379] [PMID]
10. Roosen-Runge EC, Holstein AF. The human rete testis. Cell Tissue Res 1978; 189: 409-433. [DOI:10.1007/BF00209130] [PMID]
11. França LR, Ogawa T, Avarbock MR, Brinster RL, Russell LD. Germ cell genotype controls cell cycle during spermatogenesis in the rat. Biol Reprod 1998; 59: 1371-1377. [DOI:10.1095/biolreprod59.6.1371] [PMID]
12. Kuchakulla M, Narasimman M, Khodamoradi K, Khosravizadeh Z, Ramasamy R. How defective spermatogenesis affects sperm DNA integrity. Andrologia 2020; 53: 13615. 1-11. [DOI:10.1111/and.13615]
13. Sharma R, Agarwal A. Defective spermatogenesis and sperm DNA damage. In: Zini A, Agarwal A. A clinician's guide to sperm DNA and chromatin damage. Switzeland: Springer; 2018. 229-261. [DOI:10.1007/978-3-319-71815-6_14]
14. Aitken RJ, Findlay JK, Hutt KJ, Kerr JB. Apoptosis in the germ line. Reproduction 2011; 141: 139-150. [DOI:10.1530/REP-10-0232] [PMID]
15. Rodriguez I, Ody C, Araki K, Garcia I, Vassalli P. An early and massive wave of germinal cell apoptosis is required for the development of functional spermatogenesis. EMBO J 1997; 16: 2262-2270. [DOI:10.1093/emboj/16.9.2262] [PMID] [PMCID]
16. Wang Ch, Cui YG, Wang XH, Jia Y, Sinha Hikim A, Lue YH, et al. Transient scrotal hyperthermia and levonorgestrel enhance testosterone-induced spermatogenesis suppression in men through increased germ cell apoptosis. J Clin Endocrinol Metab 2007; 92: 3292-3304. [DOI:10.1210/jc.2007-0367] [PMID]
17. Print CG, Loveland KL. Germ cell suicide: New insights into apoptosis during spermatogenesis. Bioessays 2000; 22: 423-430. https://doi.org/10.1002/(SICI)1521-1878(200005)22:5<423::AID-BIES4>3.0.CO;2-0 [DOI:10.1002/(SICI)1521-1878(200005)22:53.0.CO;2-0]
18. Aitken RJ, Koppers AJ. Apoptosis and DNA damage in human spermatozoa. Asian J Androl 2011; 13: 36-42. [DOI:10.1038/aja.2010.68] [PMID] [PMCID]
19. Abdolmaleki A, Ghayour MB, Behnam-Rassouli M. Protective effects of acetyl-l-carnitine against serum and glucose deprivation-induced apoptosis in rat adipose-derived mesenchymal stem cells. Cell Tissue Bank 2020; 21: 655-666. [DOI:10.1007/s10561-020-09844-1] [PMID]
20. Cavalcanti MCO, Steilmann C, Failing K, Bergmann M, Kliesch S, Weidner W, et al. Apoptotic gene expression in potentially fertile and subfertile men. Mol Hum Reprod 2011; 17: 415-420. [DOI:10.1093/molehr/gar011] [PMID]
21. Shukla KK, Mahdi AA, Rajender S. Apoptosis, spermatogenesis and male infertility. Front Biosci 2012; 4: 746-754. [DOI:10.2741/e415]
22. Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: Cell survival and cell death. Int J Cell Biol 2010; 2010: 214074. 1-23. [DOI:10.1155/2010/214074] [PMID] [PMCID]
23. Espino J, Mediero M, Lozano GM, Bejarano I, Ortiz Á, García JF, et al. Reduced levels of intracellular calcium releasing in spermatozoa from asthenozoospermic patients. Reprod Biol Endocrinol 2009; 7: 1-11. [DOI:10.1186/1477-7827-7-11] [PMID] [PMCID]
24. Monllor F, Espino J, Marchena AM, Ortiz A, Lozano G, García JF, et al. Melatonin diminishes oxidative damage in sperm cells, improving assisted reproductive techniques. Turk J Biol 2017; 41: 881-889. [DOI:10.3906/biy-1704-45] [PMID] [PMCID]
25. Igney FH, Krammer PH. Death and anti-death: Tumour resistance to apoptosis. Nat Rev Cancer 2002; 2: 277-288. [DOI:10.1038/nrc776] [PMID]
26. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000; 408: 307-310. [DOI:10.1038/35042675] [PMID]
27. Martinvalet D, Zhu P, Lieberman J. Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity 2005; 22: 355-370. [DOI:10.1016/j.immuni.2005.02.004] [PMID]
28. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 1992; 148: 2207-2216.
29. Marchetti C, Jouy N, Leroy-Martin B, Defossez A, Formstecher P, Marchetti Ph. Comparison of four fluorochromes for the detection of the inner mitochondrial membrane potential in human spermatozoa and their correlation with sperm motility. Hum Reprod 2004; 19: 2267-2276. [DOI:10.1093/humrep/deh416] [PMID]
30. Lozano GM, Bejarano I, Espino J, Gonzalez D, Ortiz A, Garcia JF, et al. Relationship between caspase activity and apoptotic markers in human sperm in response to hydrogen peroxide and progesterone. J Reprod Dev 2009; 55: 615-621. [DOI:10.1262/jrd.20250] [PMID]
31. Grunewald S, Sharma R, Paasch U, Glander HJ, Agarwal A. Impact of caspase activation in human spermatozoa. Microsc Res Tech 2009; 72: 878-888. [DOI:10.1002/jemt.20732] [PMID]
32. Paasch U, Grunewald S, Agarwal A, Glandera HJ. Activation pattern of caspases in human spermatozoa. Fertil Steril 2004; 81 (Suppl.): 802-809. [DOI:10.1016/j.fertnstert.2003.09.030] [PMID]
33. Salvesen GS, Dixit VM. Caspases: Intracellular signaling by proteolysis. Cell 1997; 91: 443-446. [DOI:10.1016/S0092-8674(00)80430-4]
34. Shaha C, Tripathi R, Mishra DP. Male germ cell apoptosis: Regulation and biology. Philos Trans R Soc B Biol Sci 2010; 365: 1501-1515. [DOI:10.1098/rstb.2009.0124] [PMID] [PMCID]
35. Taylor SL, Weng SL, Fox P, Duran EH, Morshedi MS, Oehninger S, et al. Somatic cell apoptosis markers and pathways in human ejaculated sperm: Potential utility as indicators of sperm quality. Mol Hum Reprod 2004; 10: 825-834. [DOI:10.1093/molehr/gah099] [PMID]
36. Grunewald S, Paasch U, Wuendrich K, Glander HJ. Sperm caspases become more activated in infertility patients than in healthy donors during cryopreservation. Arch Androl 2005; 51: 449-460. [DOI:10.1080/014850190947813] [PMID]
37. Lachaud Ch, Tesarik J, Cañadas ML, Mendoza C. Apoptosis and necrosis in human ejaculated spermatozoa. Hum Reprod 2004; 19: 607-610. [DOI:10.1093/humrep/deh130] [PMID]
38. Rajender S, Rahul P, Mahdi AA. Mitochondria, spermatogenesis and male infertility. Mitochondrion 2010; 10: 419-428. [DOI:10.1016/j.mito.2010.05.015] [PMID]
39. Adams JM. Ways of dying: Multiple pathways to apoptosis. Genes Dev 2003; 17: 2481-2495. [DOI:10.1101/gad.1126903] [PMID]
40. Sakkas D, Moffatt O, Manicardi GC, Mariethoz E, Tarozzi N, Bizzaro D. Nature of DNA damage in ejaculated human spermatozoa and the possible involvement of apoptosis. Biol Reprod 2002; 66: 1061-1067. [DOI:10.1095/biolreprod66.4.1061] [PMID]
41. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479-489. [DOI:10.1016/S0092-8674(00)80434-1]
42. Rucker EB, Dierisseau P, Wagner KU, Garrett L, Wynshaw-Boris A, Flaws JA, et al. Bcl-x and Bax regulate mouse primordial germ cell survival and apoptosis during embryogenesis. Mol Endocrinol 2000; 14: 1038-1052. [DOI:10.1210/mend.14.7.0465] [PMID]
43. Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 1995; 270: 96-99. [DOI:10.1126/science.270.5233.96] [PMID]
44. Kasai S, Chuma S, Motoyama N, Nakatsuji N. Haploinsufficiency of Bcl-x leads to male-specific defects in fetal germ cells: Differential regulation of germ cell apoptosis between the sexes. Dev Biol 2003; 264: 202-216. [DOI:10.1016/S0012-1606(03)00400-7]
45. Jeong SY, Seol DW. The role of mitochondria in apoptosis. BMB Rep 2008; 41: 11-22. [DOI:10.5483/BMBRep.2008.41.1.011] [PMID]
46. Janssen O, Qian J, Linkermann A, Kabelitz D. CD95 ligand-death factor and costimulatory molecule? Cell Death Differ 2003; 10: 1215-1225. [DOI:10.1038/sj.cdd.4401305] [PMID] [PMCID]
47. Porcelli F, Meggiolaro D, Carnevali A, Ferrandi B. Fas ligand in bull ejaculated spermatozoa: A quantitative immunocytochemical study. Acta Histochem 2006; 108: 287-292. [DOI:10.1016/j.acthis.2006.05.006] [PMID]
48. Francavilla S, D'Abrizio P, Cordeschi G, Pelliccione F, Necozione S, Ulisse S, et al. Fas expression correlates with human germ cell degeneration in meiotic and post-meiotic arrest of spermatogenesis. Mol Hum Reprod 2002; 8: 213-220. [DOI:10.1093/molehr/8.3.213] [PMID]
49. Shaha Ch. Germ cell apoptosis: Relevance to infertility and contraception. Immun Endoc Metab Agents Med Chem 2008; 8: 66-78. [DOI:10.2174/187152208783790714]
50. Sofikitis N, Giotitsas N, Tsounapi P, Baltogiannis D, Giannakis D, Pardalidis N. Hormonal regulation of spermatogenesis and spermiogenesis. J Steroid Biochem Mol Biol 2008; 109: 323-330. [DOI:10.1016/j.jsbmb.2008.03.004] [PMID]
51. Zhou XC, Wei P, Hu ZY, Gao F, Zou RJ, Liu YX. Role of Fas/FasL genes in azoospermia or oligozoospermia induced by testosterone undecanoate in rhesus monkey. Acta Pharmacol Sin 2001; 22: 1028-1033.
52. Tesarik J, Martinez F, Rienzi L, Iacobelli M, Ubaldi F, Mendoza C, et al. In-vitro effects of FSH and testosterone withdrawal on caspase activation and DNA fragmentation in different cell types of human seminiferous epithelium. Hum Reprod 2002; 17: 1811-1819. [DOI:10.1093/humrep/17.7.1811] [PMID]
53. Evenson DP. Loss of livestock breeding efficiency due to uncompensable sperm nuclear defects. Reprod Fertil Dev 1999; 11: 1-16. [DOI:10.1071/RD98023] [PMID]
54. Pareek TK, Joshi AR, Sanyal A, Dighe RR. Insights into male germ cell apoptosis due to depletion of gonadotropins caused by GnRH antagonists. Apoptosis 2007; 12: 1085-1100. [DOI:10.1007/s10495-006-0039-3] [PMID]
55. Sasagawa I, Matsuki S, Suzuki Y, Iuchi Y, Tohya K, Kimura M, et al. Possible involvement of the membrane‐bound form of peroxiredoxin 4 in acrosome formation during spermiogenesis of rats. Eur J Biochem 2001; 268: 3053-3061. [DOI:10.1046/j.1432-1327.2001.02200.x] [PMID]
56. Fujisawa M, Hiramine C, Tanaka H, Okada H, Arakawa S, Kamidono S. Decrease in apoptosis of germ cells in the testes of infertile men with varicocele. World J Urol 1999; 17: 296-300. [DOI:10.1007/s003450050149] [PMID]
57. Lee J, Richburg JH, Younkin SC, Boekelheide K. The Fas system is a key regulator of germ cell apoptosis in the testis. Endocrinology 1997; 138: 2081-2088. [DOI:10.1210/endo.138.5.5110] [PMID]
58. Pentikäinen V, Erkkilä K, Dunkel L. Fas regulates germ cell apoptosis in the human testis in vitro. Am J Physiol 1999; 276: 310-316. [DOI:10.1152/ajpendo.1999.276.2.E310] [PMID]
59. Aitken RJ, Baker MA. Causes and consequences of apoptosis in spermatozoa; contributions to infertility and impacts on development. Int J Dev Biol 2013; 57: 265-272. [DOI:10.1387/ijdb.130146ja] [PMID]
60. Agarwal A, Makker K, Sharma R. Clinical relevance of oxidative stress in male factor infertility: An update. Am J Reprod Immunol 2008; 59: 2-11. [DOI:10.1111/j.1600-0897.2007.00559.x] [PMID]
61. Vashisht A, Gahlay GK. Using miRNAs as diagnostic biomarkers for male infertility: Opportunities and challenges. Mol Hum Reprod 2020; 26: 199-214. [DOI:10.1093/molehr/gaaa016] [PMID]
62. Söderquist L, Rodriguez‐Martinez H, Janson L. Post‐thaw motility, ATP content and cytochrome C oxidase activity of AI bull spermatozoa in relation to fertility. Zentralbl Veterinarmed A 1991; 38: 165-174. [DOI:10.1111/j.1439-0442.1991.tb00998.x] [PMID]
63. Petersen CG, Mauri AL, Vagnini LD, Renzi A, Petersen B, Mattila M, et al. The effects of male age on sperm DNA damage: An evaluation of 2,178 semen samples. JBRA Assist Reprod 2018; 22: 323-330.
64. Gunes S, Hekim GNT, Arslan MA, Asci R. Effects of aging on the male reproductive system. J Assist Reprod Genet 2016; 33: 441-454. [DOI:10.1007/s10815-016-0663-y] [PMID] [PMCID]
65. Agarwal A, Said TM. Oxidative stress, DNA damage and apoptosis in male infertility: A clinical approach. BJU Int 2005; 95: 503-507. [DOI:10.1111/j.1464-410X.2005.05328.x] [PMID]
66. Aitken RJ. The amoroso lecture. The human spermatozoon-a cell in crisis? J Reprod Fertil 1999; 115: 1-7. [DOI:10.1530/jrf.0.1150001] [PMID]
67. Aziz N, Saleh RA, Sharma RK, Lewis-Jones I, Esfandiari N, Thomas Jr AJ, et al. Novel association between sperm reactive oxygen species production, sperm morphological defects, and the sperm deformity index. Fertil Steril 2004; 81: 349-354. [DOI:10.1016/j.fertnstert.2003.06.026] [PMID]
68. Agarwal A, Sharma RK, Nallella KP, Thomas Jr AJ, Alvarez JG, Sikka SC. Reactive oxygen species as an independent marker of male factor infertility. Fertil Steril 2006; 86: 878-885. [DOI:10.1016/j.fertnstert.2006.02.111] [PMID]
69. Bui AD, Sharma R, Henkel R, Agarwal A. Reactive oxygen species impact on sperm DNA and its role in male infertility. Andrologia 2018; 50: e13012. 1-10. [DOI:10.1111/and.13012] [PMID]
70. Agarwal A, Saleh RA, Bedaiwy MA. Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril 2003; 79: 829-843. [DOI:10.1016/S0015-0282(02)04948-8]
71. Sawyer DE, Mercer BG, Wiklendt AM, Aitken RJ. Quantitative analysis of gene-specific DNA damage in human spermatozoa. Mutat Res 2003; 529: 21-34. [DOI:10.1016/S0027-5107(03)00101-5]
72. Aitken RJ, Clarkson JS. Cellular basis of defective sperm function and its association with the genesis of reactive oxygen species by human spermatozoa. J Reprod Fertil 1987; 81: 459-469. [DOI:10.1530/jrf.0.0810459] [PMID]
73. Yumura Y, Iwasaki A, Saito K, Ogawa T, Hirokawa M. Effect of reactive oxygen species in semen on the pregnancy of infertile couples. Int J Urol 2009; 16: 202-207. [DOI:10.1111/j.1442-2042.2008.02213.x] [PMID]
74. Agarwal A, Mulgund A, Sharma R, Sabanegh E. Mechanisms of oligozoospermia: an oxidative stress perspective. Syst Biol Reprod Med 2014; 60: 206-216. [DOI:10.3109/19396368.2014.918675] [PMID]
75. Takeshima T, Kuroda S, Yumura Y. Reactive oxygen species and sperm cells. In: Cristiana F. Reactive oxygen species (ROS) in living cells. UK: IntechOpen; 2018. [DOI:10.5772/intechopen.73037]
76. Harlev A, Agarwal A, Gunes SO, Shetty A, du Plessis SS. Smoking and male infertility: An evidence-based review. World J Mens Health 2015; 33: 143-160. [DOI:10.5534/wjmh.2015.33.3.143] [PMID] [PMCID]
77. Sharma R, Harlev A, Agarwal A, Esteves SC. Cigarette smoking and semen quality: A new meta-analysis examining the effect of the 2010 World Health Organization laboratory methods for the examination of human semen. Eur Urol 2016; 70: 635-645. [DOI:10.1016/j.eururo.2016.04.010] [PMID]
78. Bisht S, Dada R. Oxidative stress: Major executioner in disease pathology, role in sperm DNA damage and preventive strategies. Front Biosci (Schol Ed) 2017; 9: 420-447. [DOI:10.2741/s495] [PMID]
79. Aitken RJ, Whiting S, De Iuliis GN, McClymont S, Mitchell LA, Baker MA. Electrophilic aldehydes generated by sperm metabolism activate mitochondrial reactive oxygen species generation and apoptosis by targeting succinate dehydrogenase. J Biol Chem 2012; 287: 33048-33060. [DOI:10.1074/jbc.M112.366690] [PMID] [PMCID]
80. Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 1991; 11: 81-128. [DOI:10.1016/0891-5849(91)90192-6]
81. Venkatesh S, Riyaz AM, Shamsi MB, Kumar R, Gupta NP, Mittal S, et al. Clinical significance of reactive oxygen species in semen of infertile Indian men. Andrologia 2009; 41: 251-256. [DOI:10.1111/j.1439-0272.2009.00943.x] [PMID]
82. Tesarik J, Greco E, Cohen-Bacrie P, Mendoza C. Germ cell apoptosis in men with complete and incomplete spermiogenesis failure. Mol Hum Reprod 1998; 4: 757-762. [DOI:10.1093/molehr/4.8.757] [PMID]
83. Shen HM, Dai J, Chia SE, Lim A, Ong CN. Detection of apoptotic alterations in sperm in subfertile patients and their correlations with sperm quality. Hum Reprod 2002; 17: 1266-1273. [DOI:10.1093/humrep/17.5.1266] [PMID]
84. Saleh RA, Agarwal A. Oxidative stress and male infertility: From research bench to clinical practice. J Androl 2002; 23: 737-752.
85. Xu Q, Lin HY, Yeh SD, Yu IC, Wang RS, Chen YT, et al. Infertility with defective spermatogenesis and steroidogenesis in male mice lacking androgen receptor in Leydig cells. Endocrine 2007; 32: 96-106. [DOI:10.1007/s12020-007-9015-0] [PMID]

Send email to the article author


Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Designed & Developed by : Yektaweb