Skip to main content

Advertisement

SpringerLink
Log in

Oestrogen action and male fertility: experimental and clinical findings

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

A proper balance between androgen and oestrogen is fundamental for normal male reproductive development and function in both animals and humans. This balance is governed by the cytochrome P450 aromatase, which is expressed also under spatio-temporal control. Oestrogen receptors ERα and/or ERβ, together with the membrane-associated G-protein-coupled functional ER (GPER), mediate the effects of oestrogen in the testis. Oestrogen action in male reproduction is more complex than previously predicted. The androgen/oestrogen balance and its regulation in the masculinisation programming window (MPW) during foetal life is the most critical period for the development of the male reproductive system. If this balance is impaired during the MPW, the male reproductive system may be negatively affected. Recent data from genetically modified mice and human infertile patients have shown that oestrogens may promote the engulfment of live Leydig cells by macrophages leading to male infertility. We also discuss recent data on environmental oestrogen exposure in men and rodents, where a rodent–human distinction is crucial and analyse some aspects of male fertility potentially related to impaired oestrogen/androgen balance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Lubahn DB et al (1993) Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90(23):11162–11166

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Fisher CR et al (1998) Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci USA 95(12):6965–6970

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Carani C et al (1997) Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337(2):91–95

    Article  CAS  PubMed  Google Scholar 

  4. Smith EP et al (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331(16):1056–1061

    Article  CAS  PubMed  Google Scholar 

  5. Simpson ER et al (2002) Aromatase–a brief overview. Annu Rev Physiol 64:93–127

    Article  CAS  PubMed  Google Scholar 

  6. Sharpe RM (1997) Do males rely on female hormones? Nature 390(6659):447–448

    Article  CAS  PubMed  Google Scholar 

  7. Wang RS et al (2009) Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice. Endocr Rev 30(2):119–132

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Sirianni R et al (2008) The novel estrogen receptor, G protein-coupled receptor 30, mediates the proliferative effects induced by 17beta-estradiol on mouse spermatogonial GC-1 cell line. Endocrinology 149(10):5043–5051

    Article  CAS  PubMed  Google Scholar 

  9. Toppari J et al (1996) Male reproductive health and environmental xenoestrogens. Environ Health Perspect 104(Suppl 4):741–803

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Toppari J et al (2010) Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome (TDS): environmental connection. Birth Defects Res A Clin Mol Teratol 88(10):910–919

    Article  CAS  PubMed  Google Scholar 

  11. Carlsen E et al (1992) Evidence for decreasing quality of semen during past 50 years. BMJ 305(6854):609–613

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Jørgensen N, Joensen UN, Jensen TK, Jensen MB, Almstrup K, Olesen IA, Juul A, Andersson A-M, Carlsen E, Petersen JH, Toppari J, Skakkebæk NE (2012) Human semen quality in the new millennium: a prospective cross-sectional population-based study of 4867 men. BMJ Open 2(4):e000990. doi:10.1136/bmjopen-2012-000990

    Article  PubMed Central  PubMed  Google Scholar 

  13. Welsh M et al (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 118(4):1479–1490

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Yu W et al (2014) Estrogen promotes Leydig cell engulfment by macrophages in male infertility. J Clin Invest 124(6):2709–2721

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Bulun SE et al (2005) Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 57(3):359–383

    Article  CAS  PubMed  Google Scholar 

  16. Boukari K et al (2007) Human fetal testis: source of estrogen and target of estrogen action. Hum Reprod 22(7):1885–1892

    Article  CAS  PubMed  Google Scholar 

  17. Conley A, Hinshelwood M (2001) Mammalian aromatases. Reproduction 121(5):685–695

    Article  CAS  PubMed  Google Scholar 

  18. Simpson ER et al (1994) Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev 15(3):342–355

    CAS  PubMed  Google Scholar 

  19. van den Driesche S et al (2011) Relative importance of prenatal and postnatal androgen action in determining growth of the penis and anogenital distance in the rat before, during and after puberty. Int J Androl 34(6 Pt 2):e578–e586

    Article  PubMed  CAS  Google Scholar 

  20. Dean A, Sharpe RM (2013) Anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J Clin Endocrinol Metab 98(6):2230–2238

    Article  CAS  PubMed  Google Scholar 

  21. Saez JM (1994) Leydig cells: endocrine, paracrine, and autocrine regulation. Endocr Rev 15(5):574–626

    Article  CAS  PubMed  Google Scholar 

  22. Tapanainen J et al (1981) Age-related changes in endogenous steroids of human fetal testis during early and midpregnancy. J Clin Endocrinol Metab 52(1):98–102

    Article  CAS  PubMed  Google Scholar 

  23. Pezzi V et al (2003) Profiling transcript levels for steroidogenic enzymes in fetal tissues. J Steroid Biochem Mol Biol 87(2–3):181–189

    Article  CAS  PubMed  Google Scholar 

  24. Wilhelm D, Koopman P (2006) The makings of maleness: towards an integrated view of male sexual development. Nat Rev Genet 7(8):620–631

    Article  CAS  PubMed  Google Scholar 

  25. Wyndham NR (1943) A morphological study of testicular descent. J Anat 77(Pt 2):179–188

  26. Bourguiba S et al (2003) Regulation of aromatase gene expression in Leydig cells and germ cells. J Steroid Biochem Mol Biol 86(3–5):335–343

    Article  CAS  PubMed  Google Scholar 

  27. Silandre D et al (2007) Three promoters PII, PI.f, and PI.tr direct the expression of aromatase (cyp19) gene in male rat germ cells. J Mol Endocrinol 39(2):169–181

    Article  CAS  PubMed  Google Scholar 

  28. Carreau S, Wolczynski S, Galeraud-Denis I (2010) Aromatase, oestrogens and human male reproduction. Philos Trans R Soc Lond B Biol Sci 365(1546):1571–1579

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  29. Inkster S, Yue W, Brodie A (1995) Human testicular aromatase: immunocytochemical and biochemical studies. J Clin Endocrinol Metab 80(6):1941–1947

    CAS  PubMed  Google Scholar 

  30. O’Donnell L et al (2001) Estrogen and spermatogenesis. Endocr Rev 22(3):289–318

    Article  PubMed  Google Scholar 

  31. Carreau S, Bouraima-Lelong H, Delalande C (2012) Role of estrogens in spermatogenesis. Front Biosci (Elite Ed) 4:1–11

    Article  Google Scholar 

  32. Bilinska B et al (2001) Photoperiod-dependent capability of androgen aromatization and the role of estrogens in the bank vole testis visualized by means of immunohistochemistry. Mol Cell Endocrinol 178(1–2):189–198

    Article  CAS  PubMed  Google Scholar 

  33. Aquila S et al (2002) Human ejaculated spermatozoa contain active P450 aromatase. J Clin Endocrinol Metab 87(7):3385–3390

    Article  CAS  PubMed  Google Scholar 

  34. Carreau S et al (2007) Estrogens and male reproduction: a new concept. Braz J Med Biol Res 40(6):761–768

    Article  CAS  PubMed  Google Scholar 

  35. Lambard S, Carreau S (2005) Aromatase and oestrogens in human male germ cells. Int J Androl 28(5):254–259

    Article  CAS  PubMed  Google Scholar 

  36. Nilsson S et al (2001) Mechanisms of estrogen action. Physiol Rev 81(4):1535–1565

    CAS  PubMed  Google Scholar 

  37. Hall JM, Couse JF, Korach KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 276(40):36869–36872

    Article  CAS  PubMed  Google Scholar 

  38. Matthews J, Gustafsson JA (2003) Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol Interv 3(5):281–292

    Article  CAS  PubMed  Google Scholar 

  39. Gibson DA, Saunders PT (2012) Estrogen dependent signaling in reproductive tissues—a role for estrogen receptors and estrogen related receptors. Mol Cell Endocrinol 348(2):361–372

    Article  CAS  PubMed  Google Scholar 

  40. Bjornstrom L, Sjoberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19(4):833–842

    Article  PubMed  CAS  Google Scholar 

  41. Chimento A et al (2014) GPER signaling in spermatogenesis and testicular tumors. Front Endocrinol (Lausanne) 5:30

    Google Scholar 

  42. Bjornstrom L, Sjoberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19(4):833–842

    Article  PubMed  CAS  Google Scholar 

  43. Sharpe RM (2010) Bisphenol A exposure and sexual dysfunction in men: editorial commentary on the article ‘Occupational exposure to bisphenol-A (BPA) and the risk of self-reported male sexual dysfunction’ Li et al., 2009. Hum Reprod 25(2):292–294

  44. Green S et al (1986) Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 320(6058):134–139

    Article  CAS  PubMed  Google Scholar 

  45. Kuiper GG et al (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93(12):5925–5930

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Filardo EJ et al (2000) Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 14(10):1649–1660

    Article  CAS  PubMed  Google Scholar 

  47. Wang L, Hsu CL, Chang C (2005) Androgen receptor corepressors: an overview. Prostate 63(2):117–130

    Article  CAS  PubMed  Google Scholar 

  48. Flouriot G et al (2000) Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO J 19(17):4688–4700

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Chakraborty P, Roy SK (2013) Expression of estrogen receptor alpha 36 (ESR36) in the hamster ovary throughout the estrous cycle: effects of gonadotropins. PLoS One 8(3):e58291

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Scobie GA et al (2002) Human oestrogen receptors: differential expression of ER alpha and beta and the identification of ER beta variants. Steroids 67(12):985–992

    Article  CAS  PubMed  Google Scholar 

  51. Hall JM, McDonnell DP (1999) The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 140(12):5566–5578

    CAS  PubMed  Google Scholar 

  52. Ogawa S et al (1998) Modifications of testosterone-dependent behaviors by estrogen receptor-alpha gene disruption in male mice. Endocrinology 139(12):5058–5069

    CAS  PubMed  Google Scholar 

  53. Rochira V et al (2005) Estrogens in males: what have we learned in the last 10 years? Asian J Androl 7(1):3–20

    Article  CAS  PubMed  Google Scholar 

  54. Hewitt SC, Harrell JC, Korach KS (2005) Lessons in estrogen biology from knockout and transgenic animals. Annu Rev Physiol 67:285–308

    Article  CAS  PubMed  Google Scholar 

  55. Lazari MF et al (2009) Estrogen receptors and function in the male reproductive system. Arq Bras Endocrinol Metabol 53(8):923–933

    Article  PubMed  Google Scholar 

  56. Carreau S, Hess RA (2010) Oestrogens and spermatogenesis. Philos Trans R Soc Lond B Biol Sci 365(1546):1517–1535

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Nie R et al (2002) Differential expression of estrogen receptors alpha and beta in the reproductive tracts of adult male dogs and cats. Biol Reprod 66(4):1161–1168

    Article  CAS  PubMed  Google Scholar 

  58. Zhou Q et al (2002) Localization of androgen and estrogen receptors in adult male mouse reproductive tract. J Androl 23(6):870–881

    CAS  PubMed  Google Scholar 

  59. Saunders PT et al (2001) Differential expression of oestrogen receptor alpha and beta proteins in the testes and male reproductive system of human and non-human primates. Mol Hum Reprod 7(3):227–236

    Article  CAS  PubMed  Google Scholar 

  60. Ra HS, Rubin L, Crang RF (2004) Structural impacts on thallus and algal cell components of two lichen species in response to low-level air pollution in pacific northwest forests. Microsc Microanal 10(2):270–279

    Article  CAS  PubMed  Google Scholar 

  61. Carreau S et al (2007) Estrogens: a new player in spermatogenesis. Folia Histochem Cytobiol 45(Suppl 1):S5–S10

    PubMed  Google Scholar 

  62. Jones ME et al (2007) Recognizing rare disorders: aromatase deficiency. Nat Clin Pract Endocrinol Metab 3(5):414–421

    Article  CAS  PubMed  Google Scholar 

  63. Plackett TP et al (2006) Lack of aromatase improves cell-mediated immune response after burn. Burns 32(5):577–582

    Article  PubMed  Google Scholar 

  64. Couse JE et al (2001) Molecular mechanism of estrogen action in the male: insights from the estrogen receptor null mice. Reprod Fertil Dev 13(4):211–219

    Article  CAS  PubMed  Google Scholar 

  65. Dupont S et al (2000) Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 127(19):4277–4291

    CAS  PubMed  Google Scholar 

  66. Goulding EH et al (2010) Ex3alphaERKO male infertility phenotype recapitulates the alphaERKO male phenotype. J Endocrinol 207(3):281–288

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Zhou Q et al (2001) Estrogen action and male fertility: roles of the sodium/hydrogen exchanger-3 and fluid reabsorption in reproductive tract function. Proc Natl Acad Sci USA 98(24):14132–14137

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Lee KH et al (2001) Estrogen regulation of ion transporter messenger RNA levels in mouse efferent ductules are mediated differentially through estrogen receptor (ER) alpha and ER beta. Biol Reprod 65(5):1534–1541

    Article  CAS  PubMed  Google Scholar 

  69. Mahato D et al (2000) Spermatogenic cells do not require estrogen receptor-alpha for development or function. Endocrinology 141(3):1273–1276

    CAS  PubMed  Google Scholar 

  70. Mahato D et al (2001) Estrogen receptor-alpha is required by the supporting somatic cells for spermatogenesis. Mol Cell Endocrinol 178(1–2):57–63

    Article  CAS  PubMed  Google Scholar 

  71. Couse JF et al (1995) Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. Mol Endocrinol 9(11):1441–1454

    CAS  PubMed  Google Scholar 

  72. Hewitt SC et al (2010) Estrogen-mediated regulation of Igf1 transcription and uterine growth involves direct binding of estrogen receptor alpha to estrogen-responsive elements. J Biol Chem 285(4):2676–2685

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Akingbemi BT et al (2003) Estrogen receptor-alpha gene deficiency enhances androgen biosynthesis in the mouse Leydig cell. Endocrinology 144(1):84–93

    Article  CAS  PubMed  Google Scholar 

  74. Couse JF, Korach KS (1999) Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 20(3):358–417

    Article  CAS  PubMed  Google Scholar 

  75. Antal MC et al (2008) Sterility and absence of histopathological defects in nonreproductive organs of a mouse ERbeta-null mutant. Proc Natl Acad Sci USA 105(7):2433–2438

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Winuthayanon W et al (2010) Uterine epithelial estrogen receptor alpha is dispensable for proliferation but essential for complete biological and biochemical responses. Proc Natl Acad Sci USA 107(45):19272–19277

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Bridges PJ et al (2008) Generation of Cyp17iCre transgenic mice and their application to conditionally delete estrogen receptor alpha (Esr1) from the ovary and testis. Genesis 46(9):499–505

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Billon-Gales A et al (2009) Endothelial estrogen receptor-alpha plays a crucial role in the atheroprotective action of 17beta-estradiol in low-density lipoprotein receptor-deficient mice. Circulation 120(25):2567–2576

    Article  CAS  PubMed  Google Scholar 

  79. Billon-Gales A et al (2011) Activation function 2 (AF2) of estrogen receptor-alpha is required for the atheroprotective action of estradiol but not to accelerate endothelial healing. Proc Natl Acad Sci USA 108(32):13311–13316

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Arao Y et al (2011) Estrogen receptor alpha AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators. Proc Natl Acad Sci USA 108(36):14986–14991

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Arao Y et al (2012) Transactivating function (AF) 2-mediated AF-1 activity of estrogen receptor alpha is crucial to maintain male reproductive tract function. Proc Natl Acad Sci USA 109(51):21140–21145

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Lee SY et al (2012) ERalpha/E2 signaling suppresses the expression of steroidogenic enzyme genes via cross-talk with orphan nuclear receptor Nur77 in the testes. Mol Cell Endocrinol 362(1–2):91–103

    Article  CAS  PubMed  Google Scholar 

  83. Prossnitz ER, Barton M (2011) The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 7(12):715–726

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Martensson UE et al (2009) Deletion of the G protein-coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice. Endocrinology 150(2):687–698

    Article  PubMed  CAS  Google Scholar 

  85. Otto C et al (2009) GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biol Reprod 80(1):34–41

    Article  CAS  PubMed  Google Scholar 

  86. Honda S et al (1998) Disruption of sexual behavior in male aromatase-deficient mice lacking exons 1 and 2 of the cyp19 gene. Biochem Biophys Res Commun 252(2):445–449

    Article  CAS  PubMed  Google Scholar 

  87. Robertson KM et al (2002) The phenotype of the aromatase knockout mouse reveals dietary phytoestrogens impact significantly on testis function. Endocrinology 143(8):2913–2921

    Article  CAS  PubMed  Google Scholar 

  88. Robertson KM et al (1999) Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene. Proc Natl Acad Sci USA 96(14):7986–7991

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Robertson KM et al (2001) Characterization of the fertility of male aromatase knockout mice. J Androl 22(5):825–830

    CAS  PubMed  Google Scholar 

  90. Li X et al (2001) Altered structure and function of reproductive organs in transgenic male mice overexpressing human aromatase. Endocrinology 142(6):2435–2442

    CAS  PubMed  Google Scholar 

  91. Lin W et al (2011) Molecular mechanisms of bladder outlet obstruction in transgenic male mice overexpressing aromatase (Cyp19a1). Am J Pathol 178(3):1233–1244

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Li X et al (2006) Transgenic mice expressing p450 aromatase as a model for male infertility associated with chronic inflammation in the testis. Endocrinology 147(3):1271–1277

    Article  CAS  PubMed  Google Scholar 

  93. Balasinor NH et al (2010) Effect of high intratesticular estrogen on global gene expression and testicular cell number in rats. Reprod Biol Endocrinol 8:72

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  94. Tekmal RR et al (1996) Overexpression of int-5/aromatase in mammary glands of transgenic mice results in the induction of hyperplasia and nuclear abnormalities. Cancer Res 56(14):3180–3185

    CAS  PubMed  Google Scholar 

  95. Fowler KA et al (2000) Overexpression of aromatase leads to development of testicular leydig cell tumors : an in vivo model for hormone-mediated TesticularCancer. Am J Pathol 156(1):347–353

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Mandava U, Kirma N, Tekmal RR (2001) Aromatase overexpression transgenic mice model: cell type specific expression and use of letrozole to abrogate mammary hyperplasia without affecting normal physiology. J Steroid Biochem Mol Biol 79(1–5):27–34

    Article  CAS  PubMed  Google Scholar 

  97. Qian YM et al (2001) Targeted disruption of the mouse estrogen sulfotransferase gene reveals a role of estrogen metabolism in intracrine and paracrine estrogen regulation. Endocrinology 142(12):5342–5350

    Article  CAS  PubMed  Google Scholar 

  98. Tannour-Louet M et al (2010) Identification of de novo copy number variants associated with human disorders of sexual development. PLoS ONE 5(10):e15392

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  99. Tannour-Louet M et al (2014) Increased gene copy number of VAMP7 disrupts human male urogenital development through altered estrogen action. Nat Med 20(7):715–724

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Morishima A et al (1995) Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80(12):3689–3698

    CAS  PubMed  Google Scholar 

  101. Herrmann BL et al (2002) Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. J Clin Endocrinol Metab 87(12):5476–5484

    Article  CAS  PubMed  Google Scholar 

  102. Maffei L et al (2004) Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. J Clin Endocrinol Metab 89(1):61–70

    Article  CAS  PubMed  Google Scholar 

  103. Maffei L et al (2007) A novel compound heterozygous mutation of the aromatase gene in an adult man: reinforced evidence on the relationship between congenital oestrogen deficiency, adiposity and the metabolic syndrome. Clin Endocrinol (Oxf) 67(2):218–224

    Article  CAS  Google Scholar 

  104. Bouillon R et al (2004) Estrogens are essential for male pubertal periosteal bone expansion. J Clin Endocrinol Metab 89(12):6025–6029

    Article  CAS  PubMed  Google Scholar 

  105. Lanfranco F et al (2008) A novel mutation in the human aromatase gene: insights on the relationship among serum estradiol, longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment. Bone 43(3):628–635

    Article  CAS  PubMed  Google Scholar 

  106. Mittre Herve MH, Kottler ML, Pura M (2004) Human gene mutations. Gene symbol: cYP19. Disease: aromatase deficiency. Hum Genet 114(2):224

    CAS  PubMed  Google Scholar 

  107. Deladoey J et al (1999) Aromatase deficiency caused by a novel P450arom gene mutation: impact of absent estrogen production on serum gonadotropin concentration in a boy. J Clin Endocrinol Metab 84(11):4050–4054

    CAS  PubMed  Google Scholar 

  108. Haverfield JT et al (2011) Teasing out the role of aromatase in the healthy and diseased testis. Spermatogenesis 1(3):240–249

    Article  PubMed Central  PubMed  Google Scholar 

  109. Quaynor SD et al (2013) Delayed puberty and estrogen resistance in a woman with estrogen receptor alpha variant. N Engl J Med 369(2):164–171

    Article  CAS  PubMed  Google Scholar 

  110. Shozu M, Fukami M, Ogata T (2014) Understanding the pathological manifestations of aromatase excess syndrome: lessons for clinical diagnosis. Expert Rev Endocrinol Metab 9(4):397–409

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Shozu M et al (2003) Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene. N Engl J Med 348(19):1855–1865

    Article  CAS  PubMed  Google Scholar 

  112. Simpson ER, Brown KA (2013) Obesity and breast cancer: role of inflammation and aromatase. J Mol Endocrinol 51(3):T51–T59

    Article  CAS  PubMed  Google Scholar 

  113. Scott HM, Mason JI, Sharpe RM (2009) Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds. Endocr Rev 30(7):883–925

    Article  CAS  PubMed  Google Scholar 

  114. Ra HJ, Ha JK, Kim JG (2013) One-stage revision anterior cruciate ligament reconstruction with impacted bone graft after failed primary reconstruction. Orthopedics 36(11):860–863

    Article  PubMed  Google Scholar 

  115. Fukami M, Shozu M, Ogata T (2012) Molecular bases and phenotypic determinants of aromatase excess syndrome. Int J Endocrinol 2012:584807

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  116. Ravichandran KS (2010) Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J Exp Med 207(9):1807–1817

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  117. Scott RS et al (2001) Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411(6834):207–211

    Article  CAS  PubMed  Google Scholar 

  118. Whitacre CC, Reingold SC, O’Looney PA (1999) A gender gap in autoimmunity. Science 283(5406):1277–1278

    Article  CAS  PubMed  Google Scholar 

  119. Straub RH (2007) The complex role of estrogens in inflammation. Endocr Rev 28(5):521–574

    Article  CAS  PubMed  Google Scholar 

  120. Serbina NV et al (2008) Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 26:421–452

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Calippe B et al (2010) 17Beta-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor alpha signaling in macrophages in vivo. J Immunol 185(2):1169–1176

    Article  CAS  PubMed  Google Scholar 

  122. Taylor PR et al (2005) Macrophage receptors and immune recognition. Annu Rev Immunol 23:901–944

    Article  CAS  PubMed  Google Scholar 

  123. Mo R et al (2007) GAS6 is an estrogen-inducible gene in mammary epithelial cells. Biochem Biophys Res Commun 353(1):189–194

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Wang H et al (2005) Immunoexpression of Tyro 3 family receptors–Tyro 3, Axl, and Mer–and their ligand Gas6 in postnatal developing mouse testis. J Histochem Cytochem 53(11):1355–1364

    Article  CAS  PubMed  Google Scholar 

  125. Hedger MP (2002) Macrophages and the immune responsiveness of the testis. J Reprod Immunol 57(1–2):19–34

    Article  CAS  PubMed  Google Scholar 

  126. Hutson JC (1998) Interactions between testicular macrophages and Leydig cells. J Androl 19(4):394–398

    CAS  PubMed  Google Scholar 

  127. Hales DB (2002) Testicular macrophage modulation of Leydig cell steroidogenesis. J Reprod Immunol 57(1–2):3–18

    Article  CAS  PubMed  Google Scholar 

  128. Giovannone D et al (2012) Slits affect the timely migration of neural crest cells via Robo receptor. Dev Dyn 241(8):1274–1288

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. McLachlan JA, Newbold RR, Bullock B (1975) Reproductive tract lesions in male mice exposed prenatally to diethylstilbestrol. Science 190(4218):991–992

    Article  CAS  PubMed  Google Scholar 

  130. Boisen KA et al (2005) Hypospadias in a cohort of 1072 Danish newborn boys: prevalence and relationship to placental weight, anthropometrical measurements at birth, and reproductive hormone levels at three months of age. J Clin Endocrinol Metab 90(7):4041–4046

    Article  CAS  PubMed  Google Scholar 

  131. Boisen KA et al (2004) Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet 363(9417):1264–1269

    Article  CAS  PubMed  Google Scholar 

  132. Kim MK et al (2014) Comparison of second-look arthroscopic findings and clinical results according to the amount of preserved remnant in anterior cruciate ligament reconstruction. Knee 21(3):774–778

    Article  PubMed  Google Scholar 

  133. Gioiosa L et al (2007) Developmental exposure to low-dose estrogenic endocrine disruptors alters sex differences in exploration and emotional responses in mice. Horm Behav 52(3):307–316

    Article  CAS  PubMed  Google Scholar 

  134. Cupp AS et al (2003) Effect of transient embryonic in vivo exposure to the endocrine disruptor methoxychlor on embryonic and postnatal testis development. J Androl 24(5):736–745

    Article  CAS  PubMed  Google Scholar 

  135. Aly HA, Azhar AS (2013) Methoxychlor induced biochemical alterations and disruption of spermatogenesis in adult rats. Reprod Toxicol 40:8–15

    Article  CAS  PubMed  Google Scholar 

  136. Gray LE Jr et al (1999) The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats. Toxicol Ind Health 15(1–2):37–47

    Article  PubMed  Google Scholar 

  137. Chapin RE et al (1997) The effects of perinatal/juvenile methoxychlor exposure on adult rat nervous, immune, and reproductive system function. Fundam Appl Toxicol 40(1):138–157

    Article  CAS  PubMed  Google Scholar 

  138. Du X et al (2014) Perinatal exposure to low-dose methoxychlor impairs testicular development in C57BL/6 mice. PLoS ONE 9(7):e103016

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  139. Huang C, Li X (2014) Maternal cypermethrin exposure during the perinatal period impairs testicular development in C57BL male offspring. PLoS One 9(5):e96781

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  140. Kuiper GG et al (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139(10):4252–4263

    CAS  PubMed  Google Scholar 

  141. Cao Y et al (2009) Isoflavones in urine, saliva, and blood of infants: data from a pilot study on the estrogenic activity of soy formula. J Expo Sci Environ Epidemiol 19(2):223–234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  142. Juul A et al (2014) Possible fetal determinants of male infertility. Nat Rev Endocrinol 10(9):553–562

    Article  CAS  PubMed  Google Scholar 

  143. Giwercman A (2011) Estrogens and phytoestrogens in male infertility. Curr Opin Urol 21(6):519–526

    Article  PubMed  Google Scholar 

  144. Fisch H, Braun SR (2013) Trends in global semen parameter values. Asian J Androl 15(2):169–173

    Article  PubMed Central  PubMed  Google Scholar 

  145. Travison TG et al (2007) A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab 92(1):196–202

    Article  CAS  PubMed  Google Scholar 

  146. Iwamoto T et al (2006) Semen quality of 324 fertile Japanese men. Hum Reprod 21(3):760–765

    Article  CAS  PubMed  Google Scholar 

  147. Nozawa S, Iwamoto T (2006) Effects of endocrine disrupting chemicals on male reproductive function–epidemiological views. Nihon Eiseigaku Zasshi 61(1):32–37

    Article  PubMed  Google Scholar 

  148. Buck Louis GM (2014) Persistent environmental pollutants and couple fecundity: an overview. Reproduction 147(4):R97–R104

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  149. Buck Louis GM et al (2013) Persistent environmental pollutants and couple fecundity: the LIFE study. Environ Health Perspect 121(2):231–236

    PubMed  Google Scholar 

  150. Cole DC et al (2006) Environmental contaminant levels and fecundability among non-smoking couples. Reprod Toxicol 22(1):13–19

    Article  CAS  PubMed  Google Scholar 

  151. Sanderson JT (2006) The steroid hormone biosynthesis pathway as a target for endocrine-disrupting chemicals. Toxicol Sci 94(1):3–21

    Article  CAS  PubMed  Google Scholar 

  152. Whitehead SA, Rice S (2006) Endocrine-disrupting chemicals as modulators of sex steroid synthesis. Best Pract Res Clin Endocrinol Metab 20(1):45–61

    Article  CAS  PubMed  Google Scholar 

  153. Wilson VS et al (2008) Diverse mechanisms of anti-androgen action: impact on male rat reproductive tract development. Int J Androl 31(2):178–187

    Article  CAS  PubMed  Google Scholar 

  154. Forgacs AL et al (2013) Triazine herbicides and their chlorometabolites alter steroidogenesis in BLTK1 murine Leydig cells. Toxicol Sci 134(1):155–167

    Article  CAS  PubMed  Google Scholar 

  155. Forgacs AL et al (2012) BLTK1 murine Leydig cells: a novel steroidogenic model for evaluating the effects of reproductive and developmental toxicants. Toxicol Sci 127(2):391–402

    Article  CAS  PubMed  Google Scholar 

  156. Korach KS (1994) Insights from the study of animals lacking functional estrogen receptor. Science 266(5190):1524–1527

    Article  CAS  PubMed  Google Scholar 

  157. Hess RA et al (1997) Estrogen receptor (alpha and beta) expression in the excurrent ducts of the adult male rat reproductive tract. J Androl 18(6):602–611

    CAS  PubMed  Google Scholar 

  158. Habert R et al (2014) Concerns about the widespread use of rodent models for human risk assessments of endocrine disruptors. Reproduction 147(4):R119–R129

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  159. N’Tumba-Byn T et al (2012) Differential effects of bisphenol A and diethylstilbestrol on human, rat and mouse fetal leydig cell function. PLoS ONE 7(12):e51579

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  160. Muczynski V et al (2012) Effect of mono-(2-ethylhexyl) phthalate on human and mouse fetal testis: in vitro and in vivo approaches. Toxicol Appl Pharmacol 261(1):97–104

    Article  CAS  PubMed  Google Scholar 

  161. Mitchell RT et al (2013) Diethylstilboestrol exposure does not reduce testosterone production in human fetal testis xenografts. PLoS One 8(4):e61726

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Science and Technology Major Project (2013ZX10004608), Natural Science Foundation of China (NSFC31071316 and NSFC81261130024), National Science and Technology Major Project (2012AA020601), Ministry of Science/Technology (2009CB941701), the CAU Scientific Fund (No. 2012YJ034) and Academy of Finland (No. 256433). The authors thank Dr. Andreina Kero for correcting the English language of the revised manuscript.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. State Key Laboratory of the Agro-Biotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, China

    Xiangdong Li & Lina Jia

  2. Department of Nutrition and Food Science, University of Maryland, College Park, MD, USA

    Haiwen Li

  3. Department of General Surgery, The 301th Hospital of PLA, Beijing, China

    Xiru Li

  4. Department of Physiology, Institute F Biomedicine, University of Turku, Turku, Finland

    Nafis Rahman

Authors
  1. Xiangdong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haiwen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lina Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiru Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nafis Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiangdong Li.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, X., Li, H., Jia, L. et al. Oestrogen action and male fertility: experimental and clinical findings. Cell. Mol. Life Sci. 72, 3915–3930 (2015). https://doi.org/10.1007/s00018-015-1981-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-015-1981-4

Keywords

Search

Navigation