维生素D与男性生殖的研究进展
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摘要
维生素D是一个多功能信号分子,其主要生理作用是调节机体钙磷代谢和骨的矿物化。随着研究的深入,维生素D的靶器官增多,在睾丸、男性生殖道和人类精子均有维生素D受体和维生素D代谢酶的表达,提示维生素D对生殖具有重要作用。越来越多的研究证实,维生素D缺乏或者不足与男性生殖之间存在关联。其机制可能与减少性激素水平、降低精液质量、参与生殖肿瘤发生、发展等有关。该文从维生素D代谢及生理作用、维生素D与男性生殖各方面的关系进行综述,以便探究应用维生素D预防和辅助治疗男性不育的新视角。
Vitamin D is a multifunctional signaling molecule,and its main physiological role is to regulate the body's calcium and phosphorus metabolism as well as bone mineralization. The spectrum of vitamin D target organs has been expanded,the expression of vitamin D receptor and metabolic enzymes have been found in testis,male reproductive tracts,and human spermatozoa,suggesting vitamin D plays an important role in human reproduction. More and more studies have confirmed that there is a correlation between vitamin D deficiency or insufficiency and male reproduction. The mechanism may be related to reduced levels of sex hormones,reduced semen quality,involvement in the occurrence and development of reproductive tumor,etc.Here is to make a review of the metabolism and biological role of vitamin D,as well as the relationship between vitamin D and male reproduction,in order to explore new prevention and adjuvant treatment for male infertility.
Vitamin D is a multifunctional signaling molecule,and its main physiological role is to regulate the body's calcium and phosphorus metabolism as well as bone mineralization. The spectrum of vitamin D target organs has been expanded,the expression of vitamin D receptor and metabolic enzymes have been found in testis,male reproductive tracts,and human spermatozoa,suggesting vitamin D plays an important role in human reproduction. More and more studies have confirmed that there is a correlation between vitamin D deficiency or insufficiency and male reproduction. The mechanism may be related to reduced levels of sex hormones,reduced semen quality,involvement in the occurrence and development of reproductive tumor,etc.Here is to make a review of the metabolism and biological role of vitamin D,as well as the relationship between vitamin D and male reproduction,in order to explore new prevention and adjuvant treatment for male infertility.
引文
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[3]Mahmoudi AR,Zarnani AH,Jeddi-Tehrani M,et al.Distribution of Vitamin D Receptor and 1α-Hydroxylase in male mouse reproductive tract[J].Reprod Sci,2013,20(4):426-436.
[4]Corbett ST,Hill O,Nangia AK.Vitamin D receptor found in human sperm[J].Urology,2006,68(6):1345-1349.
[5]Aquila S,Guido C,Perrotta I,et al.Human sperm anatomy:ultrastructural localization of 1α,25-dihydroxyvitamin D receptor and its possible role in the human male gamete[J].J Anat,2008,213(5):555-564.
[6]Kinuta K,Tanaka H,Moriwake T,et al.Vitamin D is an important factor in estrogen biosynthesis of both female and male gonads[J].Endocrinology,2000,141(4):1317-1324.
[7]Anagnostis P,Karras S,Goulis DG.Vitamin D in human reproduction:a narrative review[J].Int J Clin Pract,2013,67(3):225-235.
[8]Jensen MB.Vitamin D and male reproduction[J].Nat Rev Endocrinol,2014,10(3):175-186.
[9]Holick MF.Vitamin D deficiency[J].N End J Med,2007,357(3):266-281.
[10]Blomberg JM,Nielsen JE,Jorgensen A,et al.Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract[J].Hum Reprod,2010,25(5):1303-1311.
[11]Aquila S,Guido C,Middea E,et al.Human male gamete endocrinology:1alpha,25-dihydroxyvitamin D3(1,25(OH)2D3)regulates different aspects of human sperm biology and metabolism[J].Reprod Biol Endocrinol,2009,7:140.
[12]Blomberg JM,Bjerrum PJ,Jessen TE,et al.Vitamin D is positively associated with sperm motility and increases intracellular calcium in human spermatozoa[J].Hum Reprod,2011,26(6):1307-1317.
[13]Blomberg JM,Lieben L,Nielsen JE,et al.Characterization of the testicular,epididymal and endocrine phenotypes in the Leuven Vd r-deficient mouse model:targeting estrogen signalling[J].Mol Cell Endocrinol,2013,377(1/2):93-102.
[14]Costa RR,Reis RI,Aguiar JF,et al.Luteinizing hormone(LH)acts through PKA and PKC to modulate T-type calcium currents and intracellular calcium transients in mice Leydig cells[J].Cell Calcium,2011,49(3):191-199.
[15]Lee DM,Tajar A,Pye SR,et al.Association of hypogonadism with vitamin D status:the European Male Ageing Study[J].Eur J Endocrinol,2012,166(1):77-85.
[16]Wehr E,Pilz S,Boehm BO,et al.Association of vitamin D status with serum androgen levels in men[J].Clin Endocrinol(Oxf),2010,73(2):243-248.
[17]Nimptsch K,Platz EA,Willett WC,et al.Association between plasma 25-OH vitamin D and testosterone levels in men[J].Clin Endocrinol(Oxf),2012,77(1):106-112.
[18]O'Donnell L,Robertson KM,Jones ME,et al.Estrogen and spermatogenesis[J].Endocr Rev,2001,22(3):289-318.
[19]Krishnan AV,Swami S,Peng L,et al.Tissue-selective regulation of aromatase expression by calcitriol:implications for breast cancer therapy[J].Endocrinology,2010,151(1):32-42.
[20]Zanatta L,Bouraima-Lelong H,Delalande C,et al.Regulation of aromatase expression by 1α,25(OH)2vitamin D3in rat testicular cells[J].Reprod Fertil Dev,2011,23(5):725-735.
[21]Hess RA.Estrogen in the adult male reproductive tract:a review[J].Reprod Biol Endocrinol,2003,1:52.
[22]Hess RA,Bunick D,Lee KH,et al.A role for oestrogens in the male reproductive system[J].Nature,1997,390(6659):509-512.
[23]Joseph A,Hess RA,Schaeffer DJ,et al.Absence of estrogen receptor alpha leads to physiological alterations in the mouse epididymis and consequent defects in sperm function[J].Biol Reprod,2010,82(5):948-957.
[24]Hess RA,Fernandes SA,Gomes GR,et al.Estrogen and its receptors in efferent ductules and epididymis[J].J Androl,2011,32(6):600-613.
[25]Ramlau-Hansen CH,Moeller UK,Bonde JP,et al.Are serum levels of vitamin D associated with semen quality Results from a crosssectional study in young healthy men[J].Fertil Steril,2011,95(3):1000-1004.
[26]Hammoud AO,Meikle AW,Peterson CM,et al.Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters[J].Asian J Androl,2012,14(6):855-859.
[27]Wojtusik J,Johnson PA.Vitamin D regulates anti-Mullerian hormone expression in granulosa cells of the hen[J].Biol Reprod,2012,86(3):91.
[28]Blomberg JM,J rgensen A,Nielsen JE,et al.Expression of the vitamin D metabolizing enzyme CYP24A1 at the annulus of human spermatozoa may serve as a novel marker of semen quality[J].Int J Androl,2012,35(4):499-510.
[29]Yang B,Sun H,Wan Y,et al.Associations between testosterone,bone mineral density,vitamin D and semen quality in fertile and infertile Chinese men[J].Int J Androl,2012,35(6):783-792.
[30]Foresta C,Strapazzon G,De Toni L,et al.Bone mineral density and testicular failure:evidence for a role of vitamin D 25-hydroxylase in human testis[J].J Clin Endocrinol Metab,2011,96(4):646-652.
[31]Van PO,Argraves WS,Morales CR.Co-expression and interaction of cubilin and megalin in the adult male rat reproductive system[J].Mol Reprod Dev,2003,64(2):129-135.
[32]Skakkebaek NE.Possible carcinomainsitu of the testis[J].Lancet,1972,2(7776):516-517.
[33]Kraggerud SM,Hoei-Hansen CE,Alagaratnam S,et al.Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts:implications for pathogenesis[J].Endocr Rev,2013,34(3):339-376.
[34]Matusiak D,Benya RV.CYP27A1 and CYP24 expression as a function of malignant transformation in the colon[J].J Histochem Cytochem,2007,55(12):1257-1264.
[35]Blomberg JM,Andersen CB,Nielsen JE,et al.Expression of the vitamin D receptor,25-hydroxylases,1α-hydroxylase and 24-hydroxylase in the human kidney and renal clear cell cancer[J].J Steroid Biochem Mol Biol,2010,121(1/2):376-382.
[36]Fleet JC.Molecular actions of vitamin D contributing to cancer prevention[J].Mol Aspects Med,2008,29(6):388-396.
[37]Blomberg JM,J rgensen A,Nielsen JE,et al.Vitamin D metabolism and effects on pluripotency genes and cell differentiation in testicular germ cell tumors in vitro and in vivo[J].Neoplasia,2012,14(10):952-963.
[38]Jorgensen A,Blomberg JM,Nielsen JE,et al.Influence of vitamin D on cisplatin sensitivity in testicular germ cell cancer-derived cell lines and in a NTera2 xenograft model[J].J Steroid Biochem Mol Biol,2013,136:238-246.
[39]Koster R,di Pietro A,Timmer-Bosscha H,et al.Cytoplasmic p21expression levels determine cisplatin resistance in human testicular cancer[J].J Clin Invest,2010,120(10):3594-3605.
[2]Gyllenborg J,Skakkebaek NE,Nielsen NC,et al.Secular and seasonal changes in semen quality among young Danish men:a statistical analysis of semensamples from 1927 donor candidates during1977-1995[J].Int J Androl,1999,22(1):28-36.
[3]Mahmoudi AR,Zarnani AH,Jeddi-Tehrani M,et al.Distribution of Vitamin D Receptor and 1α-Hydroxylase in male mouse reproductive tract[J].Reprod Sci,2013,20(4):426-436.
[4]Corbett ST,Hill O,Nangia AK.Vitamin D receptor found in human sperm[J].Urology,2006,68(6):1345-1349.
[5]Aquila S,Guido C,Perrotta I,et al.Human sperm anatomy:ultrastructural localization of 1α,25-dihydroxyvitamin D receptor and its possible role in the human male gamete[J].J Anat,2008,213(5):555-564.
[6]Kinuta K,Tanaka H,Moriwake T,et al.Vitamin D is an important factor in estrogen biosynthesis of both female and male gonads[J].Endocrinology,2000,141(4):1317-1324.
[7]Anagnostis P,Karras S,Goulis DG.Vitamin D in human reproduction:a narrative review[J].Int J Clin Pract,2013,67(3):225-235.
[8]Jensen MB.Vitamin D and male reproduction[J].Nat Rev Endocrinol,2014,10(3):175-186.
[9]Holick MF.Vitamin D deficiency[J].N End J Med,2007,357(3):266-281.
[10]Blomberg JM,Nielsen JE,Jorgensen A,et al.Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract[J].Hum Reprod,2010,25(5):1303-1311.
[11]Aquila S,Guido C,Middea E,et al.Human male gamete endocrinology:1alpha,25-dihydroxyvitamin D3(1,25(OH)2D3)regulates different aspects of human sperm biology and metabolism[J].Reprod Biol Endocrinol,2009,7:140.
[12]Blomberg JM,Bjerrum PJ,Jessen TE,et al.Vitamin D is positively associated with sperm motility and increases intracellular calcium in human spermatozoa[J].Hum Reprod,2011,26(6):1307-1317.
[13]Blomberg JM,Lieben L,Nielsen JE,et al.Characterization of the testicular,epididymal and endocrine phenotypes in the Leuven Vd r-deficient mouse model:targeting estrogen signalling[J].Mol Cell Endocrinol,2013,377(1/2):93-102.
[14]Costa RR,Reis RI,Aguiar JF,et al.Luteinizing hormone(LH)acts through PKA and PKC to modulate T-type calcium currents and intracellular calcium transients in mice Leydig cells[J].Cell Calcium,2011,49(3):191-199.
[15]Lee DM,Tajar A,Pye SR,et al.Association of hypogonadism with vitamin D status:the European Male Ageing Study[J].Eur J Endocrinol,2012,166(1):77-85.
[16]Wehr E,Pilz S,Boehm BO,et al.Association of vitamin D status with serum androgen levels in men[J].Clin Endocrinol(Oxf),2010,73(2):243-248.
[17]Nimptsch K,Platz EA,Willett WC,et al.Association between plasma 25-OH vitamin D and testosterone levels in men[J].Clin Endocrinol(Oxf),2012,77(1):106-112.
[18]O'Donnell L,Robertson KM,Jones ME,et al.Estrogen and spermatogenesis[J].Endocr Rev,2001,22(3):289-318.
[19]Krishnan AV,Swami S,Peng L,et al.Tissue-selective regulation of aromatase expression by calcitriol:implications for breast cancer therapy[J].Endocrinology,2010,151(1):32-42.
[20]Zanatta L,Bouraima-Lelong H,Delalande C,et al.Regulation of aromatase expression by 1α,25(OH)2vitamin D3in rat testicular cells[J].Reprod Fertil Dev,2011,23(5):725-735.
[21]Hess RA.Estrogen in the adult male reproductive tract:a review[J].Reprod Biol Endocrinol,2003,1:52.
[22]Hess RA,Bunick D,Lee KH,et al.A role for oestrogens in the male reproductive system[J].Nature,1997,390(6659):509-512.
[23]Joseph A,Hess RA,Schaeffer DJ,et al.Absence of estrogen receptor alpha leads to physiological alterations in the mouse epididymis and consequent defects in sperm function[J].Biol Reprod,2010,82(5):948-957.
[24]Hess RA,Fernandes SA,Gomes GR,et al.Estrogen and its receptors in efferent ductules and epididymis[J].J Androl,2011,32(6):600-613.
[25]Ramlau-Hansen CH,Moeller UK,Bonde JP,et al.Are serum levels of vitamin D associated with semen quality Results from a crosssectional study in young healthy men[J].Fertil Steril,2011,95(3):1000-1004.
[26]Hammoud AO,Meikle AW,Peterson CM,et al.Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters[J].Asian J Androl,2012,14(6):855-859.
[27]Wojtusik J,Johnson PA.Vitamin D regulates anti-Mullerian hormone expression in granulosa cells of the hen[J].Biol Reprod,2012,86(3):91.
[28]Blomberg JM,J rgensen A,Nielsen JE,et al.Expression of the vitamin D metabolizing enzyme CYP24A1 at the annulus of human spermatozoa may serve as a novel marker of semen quality[J].Int J Androl,2012,35(4):499-510.
[29]Yang B,Sun H,Wan Y,et al.Associations between testosterone,bone mineral density,vitamin D and semen quality in fertile and infertile Chinese men[J].Int J Androl,2012,35(6):783-792.
[30]Foresta C,Strapazzon G,De Toni L,et al.Bone mineral density and testicular failure:evidence for a role of vitamin D 25-hydroxylase in human testis[J].J Clin Endocrinol Metab,2011,96(4):646-652.
[31]Van PO,Argraves WS,Morales CR.Co-expression and interaction of cubilin and megalin in the adult male rat reproductive system[J].Mol Reprod Dev,2003,64(2):129-135.
[32]Skakkebaek NE.Possible carcinomainsitu of the testis[J].Lancet,1972,2(7776):516-517.
[33]Kraggerud SM,Hoei-Hansen CE,Alagaratnam S,et al.Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts:implications for pathogenesis[J].Endocr Rev,2013,34(3):339-376.
[34]Matusiak D,Benya RV.CYP27A1 and CYP24 expression as a function of malignant transformation in the colon[J].J Histochem Cytochem,2007,55(12):1257-1264.
[35]Blomberg JM,Andersen CB,Nielsen JE,et al.Expression of the vitamin D receptor,25-hydroxylases,1α-hydroxylase and 24-hydroxylase in the human kidney and renal clear cell cancer[J].J Steroid Biochem Mol Biol,2010,121(1/2):376-382.
[36]Fleet JC.Molecular actions of vitamin D contributing to cancer prevention[J].Mol Aspects Med,2008,29(6):388-396.
[37]Blomberg JM,J rgensen A,Nielsen JE,et al.Vitamin D metabolism and effects on pluripotency genes and cell differentiation in testicular germ cell tumors in vitro and in vivo[J].Neoplasia,2012,14(10):952-963.
[38]Jorgensen A,Blomberg JM,Nielsen JE,et al.Influence of vitamin D on cisplatin sensitivity in testicular germ cell cancer-derived cell lines and in a NTera2 xenograft model[J].J Steroid Biochem Mol Biol,2013,136:238-246.
[39]Koster R,di Pietro A,Timmer-Bosscha H,et al.Cytoplasmic p21expression levels determine cisplatin resistance in human testicular cancer[J].J Clin Invest,2010,120(10):3594-3605.