Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Vitamin D and male reproduction

Nature Reviews Endocrinology volume 10, pages 175–186 (2014)Cite this article

Subjects

Key Points

  • Vitamin D is metabolized in the male reproductive organs and the expression levels of vitamin D receptor (VDR) and CYP24A1 in human spermatozoa are positive markers for semen quality

  • 1α,25-dihydroxyvitamin D3 induces a VDR-mediated increase in intracellular calcium concentration in human spermatozoa in vitro, leading to increased motility and induction of the acrosome reaction in capacitated spermatozoa

  • Vdr-null mice and rodents with vitamin D deficiency develop impaired fertility due to decreased sperm production and low sperm motility, which can only partly be restored by calcium supplementation

  • Results from human association studies are in line with those in animal models, as men with vitamin D sufficiency have a higher percentage of motile spermatozoa than men with vitamin D deficiency

  • 1α,25-dihydroxyvitamin D3 induces differentiation of embryonal carcinoma cells in vitro and in vivo and increases cellular susceptibility to cisplatin in vitro

  • The most important regulators of testicular vitamin D metabolism seem to be fibroblast growth factor 23 and Klotho, other regulators are testosterone, estradiol, calcium, phosphate and 1α,25-dihydroxyvitamin D3

Abstract

Vitamin D is a versatile signalling molecule with a well-established role in the regulation of calcium homeostasis and bone health. The spectrum of vitamin D target organs has expanded and the reproductive role of vitamin D is highlighted by expression of the vitamin D receptor (VDR) and enzymes that metabolize vitamin D in testis, male reproductive tract and human spermatozoa. The expression levels of VDR and CYP24A1 in human spermatozoa serve as positive predictive markers of semen quality, and VDR mediates a nongenomic increase in intracellular calcium concentration that induces sperm motility. Interestingly, functional animal models show that vitamin D is important for estrogen signalling and sperm motility, while cross-sectional studies support the positive association between serum 25-hydroxyvitamin D level and sperm motility in both fertile and infertile men. Expression of VDR and enzymes that metabolize vitamin D in fetal testis indicates a yet unknown role during development, which may be extrapolated from invasive testicular germ cell tumours where 1α,25-dihydroxyvitamin D induces a mesodermal differentiation of the pluripotent testicular cancer cells. Taken together, vitamin D signalling has a positive effect on semen quality, increases estrogen responsiveness and differentiates germ cell tumours. Future studies are needed to determine when 1α,25-dihydroxyvitamin D acts in a paracrine manner and whether systemic changes, which are subject to pharmacological modulation, could influence male reproductive function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Immunohistochemistry from the male reproductive organs.
Figure 2: Systemic vitamin D metabolism.
Figure 3: Factors influencing cellular vitamin D metabolism in the male reproductive organs.
Figure 4: Proposed mechanism for the nongenomic effect of VDR in human spermatozoa.

Similar content being viewed by others

References

  1. Sharpe, R. M., McKinnell, C., Kivlin, C. & Fisher, J. S. Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood. Reproduction 125, 769–784 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Mortimer, D. et al. What should it take to describe a substance or product as 'sperm-safe'. Hum. Reprod. Update 19 (Suppl. 1), i1–i45 (2013).

    Article  PubMed  Google Scholar 

  3. Bouillon, R. et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr. Rev. 29, 726–776 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Blomberg Jensen, M. et al. Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract. Hum. Reprod. 25, 1303–1311 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. van Schoor, N. M. & Lips, P. Worldwide vitamin D status. Best Pract. Res. Clin. Endocrinol. Metab. 25, 671–680 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Prosser, D. E. & Jones, G. Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem. Sci. 29, 664–673 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Haussler, M. R., Jurutka, P. W., Mizwicki, M. & Norman, A. W. Vitamin D receptor (VDR)-mediated actions of 1α, 25(OH)2 vitamin D3: genomic and non-genomic mechanisms. Best Pract. Res. Clin. Endocrinol. Metab. 25, 543–559 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Verstuyf, A., Carmeliet, G., Bouillon, R. & Mathieu, C. Vitamin D: a pleiotropic hormone. Kidney Int. 78, 140–145 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Blomberg Jensen, M. & Dissing, S. Non-genomic effects of vitamin D in human spermatozoa. Steroids 77, 903–909 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Merke, J., Kreusser, W., Bier, B. & Ritz, E. Demonstration and characterisation of a testicular receptor for 1,25-dihydroxycholecalciferol in the rat. Eur. J. Biochem. 130, 303–308 (1983).

    Article  CAS  PubMed  Google Scholar 

  12. Johnson, J. A., Grande, J. P., Roche, P. C. & Kumar, R. Immunohistochemical detection and distribution of the 1,25-dihydroxyvitamin D3 receptor in rat reproductive tissues. Histochem. Cell Biol. 105, 7–15 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Mahmoudi, A. R. et al. Distribution of vitamin D receptor and 1α-hydroxylase in male mouse reproductive tract. Reprod. Sci. 20, 426–436 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Oliveira, A. G. et al. Vitamin D3 and androgen receptors in testis and epididymal region of roosters (Gallus domesticus) as affected by epididymal lithiasis. Anim. Reprod. Sci. 109, 343–355 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Schleicher, G., Privette, T. H. & Stumpf, W. E. Distribution of soltriol [1,25(OH)2-vitamin D3] binding sites in male sex organs of the mouse: an autoradiographic study. J. Histochem. Cytochem. 37, 1083–1086 (1989).

    Article  CAS  PubMed  Google Scholar 

  16. Corbett, S. T., Hill, O. & Nangia, A. K. Vitamin D receptor found in human sperm. Urology 68, 1345–1349 (2006).

    Article  PubMed  Google Scholar 

  17. Aquila, S. et al. Human sperm anatomy: ultrastructural localization of 1α, 25-dihydroxyvitamin D receptor and its possible role in the human male gamete. J. Anat. 213, 555–564 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kidroni, G. et al. Vitamin D3 metabolites in rat epididymis: high 24,25-dihydroxy vitamin D3 levels in the cauda region. Biochem. Biophys. Res. Commun. 113, 982–989 (1983).

    Article  CAS  PubMed  Google Scholar 

  19. Erben, R. G. et al. Deletion of deoxyribonucleic acid binding domain of the vitamin D receptor abrogates genomic and nongenomic functions of vitamin D. Mol. Endocrinol. 16, 1524–1537 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Gensure, R. C., Riggle, P. C., Antrobus, S. D. & Walters, M. R. Evidence for two classes of 1,25-dihydroxyvitamin D3 binding sites in classical vs. nonclassical target tissues. Biochem. Biophys. Res. Commun. 180, 867–873 (1991).

    Article  CAS  PubMed  Google Scholar 

  21. Aquila, S. et al. Human male gamete endocrinology: 1α, 25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates different aspects of human sperm biology and metabolism. Reprod. Biol. Endocrinol. 7, 140 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Blomberg Jensen, M. et al. Vitamin D is positively associated with sperm motility and increases intracellular calcium in human spermatozoa. Hum. Reprod. 26, 1307–1317 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Blomberg Jensen, M. et al. Vitamin D metabolism and effects on pluripotency genes and cell differentiation in testicular germ cell tumors in vitro and in vivo. Neoplasia 14, 952–963 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zanatta, L., Bouraima-Lelong, H., Delalande, C., Silva, F. R. & Carreau, S. Regulation of aromatase expression by 1α, 25(OH)2 vitamin D3 in rat testicular cells. Reprod. Fertil. Dev. 23, 725–735 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Blomberg Jensen, M. et al. Characterization of the testicular, epididymal and endocrine phenotypes in the Leuven Vdr-deficient mouse model: targeting estrogen signalling. Mol. Cell Endocrinol. 377, 93–102 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Blomberg Jensen, M. 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. Int. J. Androl 35, 499–510 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Oliva, R. Protamines and male infertility. Hum. Reprod. Update 12, 417–435 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Choudhary, D., Jansson, I., Stoilov, I., Sarfarazi, M. & Schenkman, J. B. Expression patterns of mouse and human CYP orthologs (families 1–4) during development and in different adult tissues. Arch. Biochem. Biophys. 436, 50–61 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Choudhary, D., Jansson, I., Schenkman, J. B., Sarfarazi, M. & Stoilov, I. Comparative expression profiling of 40 mouse cytochrome P450 genes in embryonic and adult tissues. Arch. Biochem. Biophys. 414, 91–100 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Foresta, C. et al. Bone mineral density and testicular failure: evidence for a role of vitamin D 25-hydroxylase in human testis. J. Clin. Endocrinol. Metab 96, E646–E652 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Olson, E. B. Jr, Knutson, J. C., Bhattacharyya, M. H. & DeLuca, H. F. The effect of hepatectomy on the synthesis of 25-hydroxyvitamin D3 . J. Clin. Invest. 57, 1213–1220 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Addya, S., Zheng, Y. M., Shayiq, R. M., Fan, J. Y. & Avadhani, N. G. Characterization of a female-specific hepatic mitochondrial cytochrome P-450 whose steady-state level is modulated by testosterone. Biochemistry 30, 8323–8330 (1991).

    Article  CAS  PubMed  Google Scholar 

  33. Van, P. O., Argraves, W. S. & Morales, C. R. Co-expression and interaction of cubilin and megalin in the adult male rat reproductive system. Mol. Reprod. Dev. 64, 129–135 (2003).

    Article  CAS  Google Scholar 

  34. Clulow, J., Jones, R. C. & Hansen, L. A. Micropuncture and cannulation studies of fluid composition and transport in the ductuli efferentes testis of the rat: comparisons with the homologous metanephric proximal tubule. Exp. Physiol. 79, 915–928 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Cornwall, G. A. New insights into epididymal biology and function. Hum. Reprod. Update 15, 213–227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hess, R. A. et al. Estrogen and its receptors in efferent ductules and epididymis. J. Androl. 32, 600–613 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Weissgerber, P. et al. Male fertility depends on Ca2+ absorption by TRPV6 in epididymal epithelia. Sci. Signal. 4, ra27 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Huhtaniemi, I. & Toppari, J. Endocrine, paracrine and autocrine regulation of testicular steroidogenesis. Adv. Exp. Med. Biol. 377, 33–54 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Costa, R. R., Reis, R. I., Aguiar, J. F. & Varanda, W. A. Luteinizing hormone (LH) acts through PKA and PKC to modulate T-type calcium currents and intracellular calcium transients in mice Leydig cells. Cell Calcium 49, 191–199 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Hochberg, Z. et al. Does 1,25-dihydroxyvitamin D participate in the regulation of hormone release from endocrine glands? J. Clin. Endocrinol. Metab 60, 57–61 (1985).

    Article  CAS  PubMed  Google Scholar 

  41. Zofková, I., Scholz, G. & Stárka, L. Effect of calcitonin and 1,25(OH)2-vitamin D3 on the FSH, LH and testosterone secretion at rest and LHRH stimulated secretion. Horm. Metab. Res. 21, 682–685 (1989).

    Article  PubMed  Google Scholar 

  42. Välimäki, V. V. et al. Serum estradiol, testosterone, and sex hormone-binding globulin as regulators of peak bone mass and bone turnover rate in young Finnish men. J. Clin. Endocrinol. Metab. 89, 3785–3789 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Ramlau-Hansen, C. H., Moeller, U. K., Bonde, J. P., Olsen, J. & Thulstrup, A. M. Are serum levels of vitamin D associated with semen quality? Results from a cross-sectional study in young healthy men. Fertil. Steril. 95, 1000–1004 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Hammoud, A. O. et al. Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters. Asian J. Androl. 14, 855–859 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pilz, S. et al. Effect of vitamin D supplementation on testosterone levels in men. Horm. Metab. Res. 43, 223–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Wehr, E., Pilz, S., Boehm, B. O., Marz, W. & Obermayer-Pietsch, B. Association of vitamin D status with serum androgen levels in men. Clin. Endocrinol. (Oxf.) 73, 243–248 (2010).

    Article  CAS  Google Scholar 

  47. Lee, D. M. et al. Association of hypogonadism with vitamin D status: the European Male Ageing Study. Eur. J. Endocrinol. 166, 77–85 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Nimptsch, K., Platz, E. A., Willett, W. C. & Giovannucci, E. Association between plasma 25-OH vitamin D and testosterone levels in men. Clin. Endocrinol. (Oxf.) 77, 106–112 (2012).

    Article  CAS  Google Scholar 

  49. Andersson, A. M., Carlsen, E., Petersen, J. H. & Skakkebaek, N. E. Variation in levels of serum inhibin B, testosterone, estradiol, luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin in monthly samples from healthy men during a 17-month period: possible effects of seasons. J. Clin. Endocrinol. Metab. 88, 932–937 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Chen, R. Y. et al. Relationship between calcium absorption and plasma dehydroepiandrosterone sulphate (DHEAS) in healthy males. Clin. Endocrinol. (Oxf.) 69, 864–869 (2008).

    Article  CAS  Google Scholar 

  51. Sonnenberg, J., Luine, V. N., Krey, L. C. & Christakos, S. 1,25-Dihydroxyvitamin D3 treatment results in increased choline acetyltransferase activity in specific brain nuclei. Endocrinology 118, 1433–1439 (1986).

    Article  CAS  PubMed  Google Scholar 

  52. Inpanbutr, N., Reiswig, J. D., Bacon, W. L., Slemons, R. D. & Iacopino, A. M. Effect of vitamin D on testicular CaBP28K expression and serum testosterone in chickens. Biol. Reprod. 54, 242–248 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Oury, F. et al. Endocrine regulation of male fertility by the skeleton. Cell 144, 796–809 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pi, M. et al. GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. PLoS ONE 3, e3858 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Johansen, J. S. et al. Serum bone Gla-protein as a marker of bone growth in children and adolescents: correlation with age, height, serum insulin-like growth factor I, and serum testosterone. J. Clin. Endocrinol. Metab. 67, 273–278 (1988).

    Article  CAS  PubMed  Google Scholar 

  56. Bolland, M. J., Grey, A., Horne, A. M. & Reid, I. R. Testosterone levels following decreases in serum osteocalcin. Calcif. Tissue Int. 93, 133–136 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Krishnan, A. V. et al. Tissue-selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy. Endocrinology 151, 32–42 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. O'Donnell, L., Robertson, K. M., Jones, M. E. & Simpson, E. R. Estrogen and spermatogenesis. Endocr. Rev. 22, 289–318 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Hess, R. A. Estrogen in the adult male reproductive tract: a review. Reprod. Biol. Endocrinol. 1, 52 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kinuta, K. et al. Vitamin D is an important factor in estrogen biosynthesis of both female and male gonads. Endocrinology 141, 1317–1324 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Bulun, S. E. et al. Use of tissue-specific promoters in the regulation of aromatase cytochrome P450 gene expression in human testicular and ovarian sex cord tumors, as well as in normal fetal and adult gonads. J. Clin. Endocrinol. Metab. 78, 1616–1621 (1994).

    CAS  PubMed  Google Scholar 

  62. Lanzino, M. et al. Aromatase messenger RNA is derived from the proximal promoter of the aromatase gene in Leydig, Sertoli, and germ cells of the rat testis. Biol. Reprod. 64, 1439–1443 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Carreau, S., Bourguiba, S., Lambard, S., Silandre, D. & Delalande, C. The promoter(s) of the aromatase gene in male testicular cells. Reprod. Biol. 4, 23–34 (2004).

    PubMed  Google Scholar 

  64. Kato, S. et al. A calcium-deficient diet caused decreased bone mineral density and secondary elevation of estrogen in aged male rats—effect of menatetrenone and elcatonin. Metabolism 51, 1230–1234 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Hess, R. A. et al. A role for oestrogens in the male reproductive system. Nature 390, 509–512 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Joseph, A. et al. Absence of estrogen receptor alpha leads to physiological alterations in the mouse epididymis and consequent defects in sperm function. Biol. Reprod. 82, 948–957 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Andersson, A. M., Petersen, J. H., Jorgensen, N., Jensen, T. K. & Skakkebaek, N. E. Serum inhibin B and follicle-stimulating hormone levels as tools in the evaluation of infertile men: significance of adequate reference values from proven fertile men. J. Clin. Endocrinol. Metab. 89, 2873–2879 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Dennis, N. A. et al. The level of serum anti-Müllerian hormone correlates with vitamin D status in men and women but not in boys. J. Clin. Endocrinol. Metab 97, 2450–2455 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Malloy, P. J., Peng, L., Wang, J. & Feldman, D. Interaction of the vitamin D receptor with a vitamin D response element in the Mullerian-inhibiting substance (MIS) promoter: regulation of MIS expression by calcitriol in prostate cancer cells. Endocrinology 150, 1580–1587 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Nef, S. & Parada, L. F. Cryptorchidism in mice mutant for Insl3. Nat. Genet. 22, 295–299 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Parikh, G. et al. Vitamin D regulates steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production in human ovarian cells. Horm. Metab. Res. 42, 754–757 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Skakkebaek, N. E., Giwercman, A. & de Kretser, D. Pathogenesis and management of male infertility. Lancet 343, 1473–1479 (1994).

    Article  CAS  PubMed  Google Scholar 

  73. Kwiecinski, G. G., Petrie, G. I. & DeLuca, H. F. Vitamin D is necessary for reproductive functions of the male rat. J. Nutr. 119, 741–744 (1989).

    Article  CAS  PubMed  Google Scholar 

  74. Uhland, A. M., Kwiecinski, G. G. & DeLuca, H. F. Normalization of serum calcium restores fertility in vitamin D-deficient male rats. J. Nutr. 122, 1338–1344 (1992).

    Article  CAS  PubMed  Google Scholar 

  75. Blomberg Jensen, M. Vitamin D metabolism, sex hormones, and male reproductive function. Reproduction 144, 135–152 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Audet, I., Laforest, J. P., Martineau, G. P. & Matte, J. J. Effect of vitamin supplements on some aspects of performance, vitamin status, and semen quality in boars. J. Anim. Sci. 82, 626–633 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Sood, S., Reghunandanan, R., Reghunandanan, V., Marya, R. K. & Singh, P. I. Effect of vitamin D repletion on testicular function in vitamin D-deficient rats. Ann. Nutr. Metab. 39, 95–98 (1995).

    Article  CAS  PubMed  Google Scholar 

  78. Hamden, K. et al. Inhibitory effects of 1α, 25dihydroxyvitamin D3 and Ajuga iva extract on oxidative stress, toxicity and hypo-fertility in diabetic rat testes. J. Physiol. Biochem. 64, 231–239 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Yang, B. et al. Associations between testosterone, bone mineral density, vitamin D and semen quality in fertile and infertile Chinese men. Int. J. Androl. 35, 783–792 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Naaby-Hansen, S. et al. Co-localization of the inositol 1,4,5-trisphosphate receptor and calreticulin in the equatorial segment and in membrane bounded vesicles in the cytoplasmic droplet of human spermatozoa. Mol. Hum. Reprod. 7, 923–933 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Norman, A. W. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am. J. Clin. Nutr. 88, 491S–499S (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Blomberg Jensen, M. Active vitamin D or analogs thereof for use in in vivo or in vitro fertilization. Patent application (WO/2012/116699).

  83. Rojansky, N., Brzezinski, A. & Schenker, J. G. Seasonality in human reproduction: an update. Hum. Reprod. 7, 735–745 (1992).

    Article  CAS  PubMed  Google Scholar 

  84. Chaganti, R. S. & Houldsworth, J. Genetics and biology of adult human male germ cell tumors. Cancer Res. 60, 1475–1482 (2000).

    CAS  PubMed  Google Scholar 

  85. Skakkebaek, N. E. Possible carcinoma-in-situ of the testis. Lancet 2, 516–517 (1972).

    Article  CAS  PubMed  Google Scholar 

  86. Sonne, S. B. et al. Analysis of gene expression profiles of microdissected cell populations indicates that testicular carcinoma in situ is an arrested gonocyte. Cancer Res. 69, 5241–5250 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kraggerud, S. M. et al. Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts: implications for pathogenesis. Endocr. Rev. 34, 339–376 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Matusiak, D. & Benya, R. V. CYP27A1 and CYP24 expression as a function of malignant transformation in the colon. J. Histochem. Cytochem. 55, 1257–1264 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Blomberg Jensen M. 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. Steroid Biochem. Mol. Biol. 121, 376–382 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Fleet, J. C. Molecular actions of vitamin D contributing to cancer prevention. Mol. Aspects Med. 29, 388–396 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. De Jong, B. W. et al. Raman spectroscopic analysis identifies testicular microlithiasis as intratubular hydroxyapatite. J. Urol. 171, 92–96 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Holm, M., Lenz, S., De Meyts, E. R. & Skakkebaek, N. E. Microcalcifications and carcinoma in situ of the testis. BJU Int. 87, 144–149 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Jorgensen, A., Blomberg, J. M., Nielsen, J. E., Juul, A. & Rajpert-de, M. E. Influence of vitamin D on cisplatin sensitivity in testicular germ cell cancer-derived cell lines and in a NTera2 xenograft model. J. Steroid Biochem. Mol. Biol. 136, 238–246 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Koster, R. et al. Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer. J. Clin. Invest. 120, 3594–3605 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Feldman, D. R., Bosl, G. J., Sheinfeld, J. & Motzer, R. J. Medical treatment of advanced testicular cancer. JAMA 299, 672–684 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Nyomba, B. L., Bouillon, R. & De Moor, P. Evidence for an interaction of insulin and sex steroids in the regulation of vitamin D metabolism in the rat. J. Endocrinol. 115, 295–301 (1987).

    Article  CAS  PubMed  Google Scholar 

  97. Henry, H. L. Regulation of vitamin D metabolism. Best Pract. Res. Clin. Endocrinol. Metab. 25, 531–541 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Chanakul, A. et al. FGF-23 regulates CYP27B1 transcription in the kidney and in extra-renal tissues. PLoS ONE 8, e72816 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Li, S. A. et al. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct. Funct. 29, 91–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Imai, M. et al. Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1α-hydroxylase gene expression. Endocrine 25, 229–234 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Razzaque, M. S. & Lanske, B. The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. J. Endocrinol. 194, 1–10 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Steger, K., Tetens, F., Seitz, J., Grothe, C. & Bergmann, M. Localization of fibroblast growth factor 2 (FGF-2) protein and the receptors FGFR 1–4 in normal human seminiferous epithelium. Histochem. Cell Biol. 110, 57–62 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Lanske, B. & Razzaque, M. S. Premature aging in klotho mutant mice: cause or consequence? Ageing Res. Rev. 6, 73–79 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Usdin, T. B. et al. Tuberoinfundibular peptide of 39 residues is required for germ cell development. Endocrinology 149, 4292–4300 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Czykier, E., Zabel, M. & Surdyk-Zasada, J. Immunolocalization of PTHrP in prepubertal and pubertal testis of European bison. Folia Histochem. Cytobiol. 40, 373–375 (2002).

    PubMed  Google Scholar 

  107. Pondel, M. Calcitonin and calcitonin receptors: bone and beyond. Int. J. Exp. Pathol. 81, 405–422 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Saarem, K. & Pedersen, J. I. Effect of age, gonadectomy and hypophysectomy on mitochondrial hydroxylation of vitamin D3 (cholecalciferol) and of 5β-cholestane-3α, 7α, 12α-triol in female and male rat liver. Biochem. J. 251, 475–481 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Saarem, K. & Pedersen, J. I. Sex differences in the hydroxylation of cholecalciferol and of 5β-cholestane-3α, 7α, 12α-triol in rat liver. Biochem. J. 247, 73–78 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Small, M., Beastall, G. H., Semple, C. G., Cowan, R. A. & Forbes, C. D. Alteration of hormone levels in normal males given the anabolic steroid stanozolol. Clin. Endocrinol. (Oxf.) 21, 49–55 (1984).

    Article  CAS  Google Scholar 

  111. Saunders, P. T. et al. Differential expression of oestrogen receptor α and β proteins in the testes and male reproductive system of human and non-human primates. Mol. Hum. Reprod. 7, 227–236 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Joseph, A., Shur, B. D. & Hess, R. A. Estrogen, efferent ductules, and the epididymis. Biol. Reprod. 84, 207–217 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Tanaka, Y., Castillo, L. & DeLuca, H. F. Control of renal vitamin D hydroxylases in birds by sex hormones. Proc. Natl Acad. Sci. USA 73, 2701–2705 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Nangia, A. K., Hill, O., Waterman, M. D., Schwender, C. E. & Memoli, V. Testicular maturation arrest to testis cancer: spectrum of expression of the vitamin D receptor and vitamin D treatment in vitro. J. Urol. 178, 1092–1096 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Kim, M. S. et al. DNA demethylation in hormone-induced transcriptional derepression. Nature 461, 1007–1012 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Chen, K. S. & DeLuca, H. F. Cloning of the human 1α,25-dihydroxyvitamin D-3 24-hydroxylase gene promoter and identification of two vitamin D-responsive elements. Biochim. Biophys. Acta 1263, 1–9 (1995).

    Article  PubMed  Google Scholar 

  117. Gensure, R. C. et al. Homologous up-regulation of vitamin D receptors is tissue specific in the rat. J. Bone Miner. Res. 13, 454–463 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Muller, D. et al. Molecular cloning, tissue distribution, and chromosomal mapping of the human epithelial Ca2+ channel (ECAC1). Genomics 67, 48–53 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Schuh, K. et al. Plasma membrane Ca2+ ATPase 4 is required for sperm motility and male fertility. J. Biol. Chem. 279, 28220–28226 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Shiba, K. et al. Na+/Ca2+ exchanger modulates the flagellar wave pattern for the regulation of motility activation and chemotaxis in the ascidian spermatozoa. Cell Motil. Cytoskeleton 63, 623–632 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Corut, A. et al. Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am. J. Hum. Genet. 79, 650–656 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hinson, T. K. et al. Identification of putative transmembrane receptor sequences homologous to the calcium-sensing G-protein-coupled receptor. Genomics 45, 279–289 (1997).

    Article  CAS  PubMed  Google Scholar 

  123. Saini, R. K. et al. 1,25-dihydroxyvitamin D3 regulation of fibroblast growth factor-23 expression in bone cells: evidence for primary and secondary mechanisms modulated by leptin and interleukin-6. Calcif. Tissue Int. 92, 339–353 (2013).

    Article  CAS  PubMed  Google Scholar 

  124. Forster, R. E. et al. Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells. Biochem. Biophys. Res. Commun. 414, 557–562 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Shimasaki, S., Koba, A., Mercado, M., Shimonaka, M. & Ling, N. Complementary DNA structure of the high molecular weight rat insulin-like growth factor binding protein (IGF-BP3) and tissue distribution of its mRNA. Biochem. Biophys. Res. Commun. 165, 907–912 (1989).

    Article  CAS  PubMed  Google Scholar 

  126. Hirai, T. et al. Effect of 1,25-dihydroxyvitamin D on testicular morphology and gene expression in experimental cryptorchid mouse: testis specific cDNA microarray analysis and potential implication in male infertility. J. Urol. 181, 1487–1492 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Zanatta, L. et al. Effect of 1α, 25-dihydroxyvitamin D3 in plasma membrane targets in immature rat testis: ionic channels and gamma-glutamyl transpeptidase activity. Arch. Biochem. Biophys. 515, 46–53 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Rosso, A. et al. 1α, 25(OH)2-vitamin D3 stimulates rapid plasma membrane calcium influx via MAPK activation in immature rat Sertoli cells. Biochimie 94, 146–154 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. Panda, D. K. et al. Targeted ablation of the 25-hydroxyvitamin D 1α-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc. Natl Acad. Sci. USA 98, 7498–7503 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Oury F. et al. Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. J. Clin. Invest. 123, 2421–2433 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Jeong, J. H. et al. Expression of Runx2 transcription factor in non-skeletal tissues, sperm and brain. J. Cell Physiol. 217, 511–517 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I am very grateful to S. Dissing, N. E. Skakkebaek, A. Juul, A. Jørgensen, J. E. Nielsen, T. Svingen and especially E. Rajpert De-Meyts for constructive comments.

Author information

Authors and Affiliations

  1. University Department of Growth and Reproduction, Rigshospitalet, Section 5064, Blegdamsvej 9, Copenhagen, 2100, Denmark

    Martin Blomberg Jensen

Authors
  1. Martin Blomberg Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Blomberg Jensen.

Ethics declarations

Competing interests

The author declares that he holds two patent applications related to vitamin D and reproduction (patent WO/1016/17116 and WO/2012/116699).

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jensen, M. Vitamin D and male reproduction. Nat Rev Endocrinol 10, 175–186 (2014). https://doi.org/10.1038/nrendo.2013.262

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2013.262

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing