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Physiology of Testosterone Production

  • Joseph W. McQuaid
  • Cigdem Tanrikut
Chapter

Abstract

Androgens play an essential role in the development of male reproductive organs, the maintenance of male fertility, and the preservation of secondary male sexual characteristics. The production of testosterone, the dominant circulating androgen, is a finely balanced process with many points of potential regulation, starting with the translocation of cholesterol across the mitochondrial membrane and ending with the negative feedback of testosterone at level of the hypothalamus and the pituitary gland. This chapter explores the physiology of testosterone production, beginning with its intracellular synthesis and steroidogenic conversion, and then follows testosterone’s transport across the cell membrane and into circulation. Regulation of this system via the hypothalamic–pituitary–testis axis is reviewed. Finally, this discussion concludes with two increasingly prevalent clinical circumstances in which testosterone physiology is altered: the metabolic syndrome and the aging male.

Keywords

Luteinizing Hormone Sertoli Cell Leydig Cell Congenital Adrenal Hyperplasia Luteinizing Hormone Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Brown-Sequard CE. The effects produced on man by subcutaneous injections of liquid obtained from the testicles of animals. Lancet. 1889;134(3438):3.CrossRefGoogle Scholar
  2. 2.
    Freeman ER, Bloom DA, McGuire EJ. A brief history of testosterone. J Urol. 2001;165(2):371–3.PubMedCrossRefGoogle Scholar
  3. 3.
    Petersen PM, Pakkenberg B. Stereological quantification of Leydig and Sertoli cells in the testis of old and young men. Image Anal Stereol. 2000;19(3):215–8.CrossRefGoogle Scholar
  4. 4.
    Lejeune H, Habert R, Saez JM. Origin, proliferation and differentiation of Leydig cells. J Mol Endocrinol. 1998;20(1):1–25.PubMedCrossRefGoogle Scholar
  5. 5.
    Nistal M, Paniagua R, Regadera J, et al. A quantitative morphological study of human Leydig cells from birth to adulthood. Cell Tissue Res. 1986;246(2):229–36.PubMedCrossRefGoogle Scholar
  6. 6.
    Prince FP. Ultrastructural evidence of mature Leydig cells and Leydig cell regression in the neonatal human testis. Anat Rec. 1990;228(4):405–17.PubMedCrossRefGoogle Scholar
  7. 7.
    Weinbauer G, Gromoll J, Simoni M, et al. Physiology of Testicular Function. In: Nieschlag E, Behre HM, Ahlen HV, editors. Andrology: male reproductive health and dysfunction. 2nd ed. New York: Springer; 2001.Google Scholar
  8. 8.
    Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev. 2004;25(6):947–70.PubMedCrossRefGoogle Scholar
  9. 9.
    Clark BJ, Stocco DM. Steroidogenic acute regulatory protein: the StAR still shines brightly. Mol Cell Endocrinol. 1997;134(1):1–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Manna PR, Dyson MT, Stocco DM. Regulation of the steroidogenic acute regulatory protein gene expression: present and future perspectives. Mol Hum Reprod. 2009;15(6):321–33.PubMedCrossRefGoogle Scholar
  11. 11.
    Lin D, Sugawara T, Strauss III JF, et al. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science. 1995;267(5205):1828–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Nakajin S, Shively JE, Yuan PM, et al. Microsomal cytochrome P-450 from neonatal pig testis: two enzymatic activities (17 alpha-hydroxylase and c17,20-lyase) associated with one protein. Biochemistry. 1981;20(14):4037–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Brock BJ, Waterman MR. Biochemical differences between rat and human cytochrome P450c17 support the different steroidogenic needs of these two species. Biochemistry. 1999;38(5):1598–606.PubMedCrossRefGoogle Scholar
  14. 14.
    Mendel CM. The free hormone hypothesis. Distinction from the free hormone transport hypothesis. J Androl. 1992;13(2):107–16.PubMedGoogle Scholar
  15. 15.
    Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666–72.PubMedCrossRefGoogle Scholar
  16. 16.
    Willnow TE, Nykjaer A. Cellular uptake of steroid carrier proteins—mechanisms and implications. Mol Cell Endocrinol. 2010;316(1):93–102.PubMedCrossRefGoogle Scholar
  17. 17.
    Jin Y, Penning TM. Steroid 5alpha-reductases and 3alpha-hydroxysteroid dehydrogenases: key enzymes in androgen metabolism. Best Pract Res Clin Endocrinol Metab. 2001;15(1):79–94.PubMedCrossRefGoogle Scholar
  18. 18.
    El-Awady MK, El-Garf W, El-Houssieny L. Steroid 5alpha reductase mRNA type 1 is differentially regulated by androgens and glucocorticoids in the rat liver. Endocr J. 2004;51(1):37–46.PubMedCrossRefGoogle Scholar
  19. 19.
    Hayes FJ, Crowley Jr WF. Gonadotropin pulsations across development. Horm Res. 1998;49(3–4):163–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Matsumoto AM, Gross KM, Bremner WJ. The physiological significance of pulsatile LHRH secretion in man: gonadotrophin responses to physiological doses of pulsatile versus continuous LHRH administration. Int J Androl. 1991;14(1):23–32.PubMedCrossRefGoogle Scholar
  21. 21.
    Delemarre-van de Waal HA. Regulation of puberty. Best Pract Res Clin Endocrinol Metab. 2002;16(1):1–12.PubMedCrossRefGoogle Scholar
  22. 22.
    Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev. 2002;23(2):141–74.PubMedCrossRefGoogle Scholar
  23. 23.
    Dufau ML. Endocrine regulation and communicating functions of the Leydig cell. Annu Rev Physiol. 1988;50:483–508.PubMedCrossRefGoogle Scholar
  24. 24.
    Baker J, Hardy MP, Zhou J, et al. Effects of an Igf1 gene null mutation on mouse reproduction. Mol Endocrinol. 1996;10(7):903–18.PubMedGoogle Scholar
  25. 25.
    Hu GX, Lin H, Chen GR, et al. Deletion of the Igf1 gene: suppressive effects on adult Leydig cell development. J Androl. 2010;31(4):379–87.PubMedCrossRefGoogle Scholar
  26. 26.
    Lui WY, Lee WM, Cheng CY. TGF-betas: their role in testicular function and Sertoli cell tight junction dynamics. Int J Androl. 2003;26(3):147–60.PubMedCrossRefGoogle Scholar
  27. 27.
    Svechnikov K, Landreh L, Weisser J, et al. Origin, development and regulation of human Leydig cells. Horm Res Paediatr. 2010;73(2):93–101.PubMedCrossRefGoogle Scholar
  28. 28.
    Wikstrom AM, Bay K, Hero M, et al. Serum insulin-like factor 3 levels during puberty in healthy boys and boys with Klinefelter syndrome. J Clin Endocrinol Metab. 2006;91(11):4705–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Bay K, Hartung S, Ivell R, et al. Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders: relationship to the luteinizing hormone-testosterone axis. J Clin Endocrinol Metab. 2005;90(6):3410–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Foresta C, Bettella A, Vinanzi C, et al. A novel circulating hormone of testis origin in humans. J Clin Endocrinol Metab. 2004;89(12):5952–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Ivell R, Wade JD, Anand-Ivell R. INSL3 as a biomarker of Leydig cell functionality. Biol Reprod. 2013;88(6):147.PubMedCrossRefGoogle Scholar
  32. 32.
    Zhu CC, Zhang H, Zhang JS, et al. Inhibition of ghrelin signaling improves the reproductive phenotype of male ob/ob mouse. Fertil Steril. 2013;99(3):918–26.PubMedCrossRefGoogle Scholar
  33. 33.
    Sirotkin AV, Chrenkova M, Nitrayova S, et al. Effects of chronic food restriction and treatments with leptin or ghrelin on different reproductive parameters of male rats. Peptides. 2008;29(8):1362–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Sun Y, Asnicar M, Saha PK, et al. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab. 2006;3(5):379–86.PubMedCrossRefGoogle Scholar
  35. 35.
    Fernandez-Fernandez R, Tena-Sempere M, Navarro VM, et al. Effects of ghrelin upon gonadotropin-releasing hormone and gonadotropin secretion in adult female rats: in vivo and in vitro studies. Neuroendocrinology. 2005;82(5–6):245–55.PubMedGoogle Scholar
  36. 36.
    Tena-Sempere M. Ghrelin as a pleotrophic modulator of gonadal function and reproduction. Nat Clin Pract Endocrinol Metab. 2008;4(12):666–74.PubMedCrossRefGoogle Scholar
  37. 37.
    Ishikawa T, Fujioka H, Ishimura T, et al. Ghrelin expression in human testis and serum testosterone level. J Androl. 2007;28(2):320–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Pitteloud N, Dwyer AA, DeCruz S, et al. Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab. 2008;93(3):784–91.PubMedCrossRefGoogle Scholar
  39. 39.
    Popkin BM, Adair LS, Ng SW. Global nutrition transition and the pandemic of obesity in developing countries. Nutr Rev. 2012;70(1):3–21.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Montague CT, O’Rahilly S. The perils of portliness: causes and consequences of visceral adiposity. Diabetes. 2000;49(6):883–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Zitzmann M, Nieschlag E. Effects of androgen replacement on metabolism and physical performances in male hypogonadism. J Endocrinol Invest. 2003;26(9):886–92.PubMedGoogle Scholar
  42. 42.
    De Maddalena C, Vodo S, Petroni A, et al. Impact of testosterone on body fat composition. J Cell Physiol. 2012;227(12):3744–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Walker BR. Steroid metabolism in metabolic syndrome X. Best Pract Res Clin Endocrinol Metab. 2001;15(1):111–22.PubMedCrossRefGoogle Scholar
  44. 44.
    Al-Harithy RN. Relationship of leptin concentration to gender, body mass index and age in Saudi adults. Saudi Med J. 2004;25(8):1086–90.PubMedGoogle Scholar
  45. 45.
    Luukkaa V, Pesonen U, Huhtaniemi I, et al. Inverse correlation between serum testosterone and leptin in men. J Clin Endocrinol Metab. 1998;83(9):3243–6.PubMedGoogle Scholar
  46. 46.
    Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92(11):4241–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004;27(5):1036–41.PubMedCrossRefGoogle Scholar
  48. 48.
    Araujo AB, O’Donnell AB, Brambilla DJ, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2004;89(12):5920–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Harkonen K, Huhtaniemi I, Makinen J, et al. The polymorphic androgen receptor gene CAG repeat, pituitary-testicular function and andropausal symptoms in ageing men. Int J Androl. 2003;26(3):187–94.PubMedCrossRefGoogle Scholar
  50. 50.
    Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994;22(15):3181–6.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Beilin J, Ball EM, Favaloro JM, et al. Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. J Mol Endocrinol. 2000;25(1):85–96.PubMedCrossRefGoogle Scholar
  52. 52.
    Liu CC, Lee YC, Wang CJ, et al. The impact of androgen receptor CAG repeat polymorphism on andropausal symptoms in different serum testosterone levels. J Sex Med. 2012;9(9):2429–37.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of UrologyMassachusetts General HospitalBostonUSA
  2. 2.Department of UrologyMGH Fertility Center, Massachusetts General Hospital, Harvard Medical SchoolBostonUSA

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