Skip to main content
SpringerLink
Log in
Book cover

Biennial Review of Infertility pp 21–28Cite as

Metformin for the Treatment of Polycystic Ovary Syndrome (PCOS)

  • Chapter
  • First Online:

  • 623 Accesses

Abstract

Because of the high prevalence of insulin resistance, there is a growing interest in the application of insulin sensitizing agents in patients with polycystic ovary syndrome (PCOS). Metformin is the most widely prescribed insulin sensitizing agent in patients with PCOS. In this chapter, we address the importance of lifestyle modification as the initial intervention in patients with PCOS. Furthermore, we discuss the efficacy of metformin compared to low-dose estrogen/progestin oral contraceptives in restoring menstrual cyclicity, reducing androgen excess, and protecting against uterine malignancies. Additionally, the role of metformin in PCOS patients with infertility is addressed.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Hull MG. Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol 1987;1:235–45.

    Article  PubMed  CAS  Google Scholar 

  2. Polson DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries–a common finding in normal women. Lancet 1988;1:870–2.

    Article  PubMed  CAS  Google Scholar 

  3. Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000;85:2434–8.

    Article  PubMed  CAS  Google Scholar 

  4. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853–61.

    Article  PubMed  CAS  Google Scholar 

  5. Lam PM, Cheung LP, Haines C. Revisit of metformin treatment in polycystic ovarian syndrome. Gynecol Endocrinol 2004;19:33–9.

    Article  PubMed  CAS  Google Scholar 

  6. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41–7.

    Google Scholar 

  7. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223–36.

    Article  PubMed  CAS  Google Scholar 

  8. Hardiman P, Pillay OC, Atiomo W. Polycystic ovary ­syndrome and endometrial carcinoma. Lancet 2003;361:1810–2.

    Article  PubMed  Google Scholar 

  9. 9.Gadducci A, Gargini A, Palla E, Fanucchi A, Genazzani AR. Polycystic ovary syndrome and gynecological cancers: is there a link? Gynecol Endocrinol 2005;20:200–8.

    Article  PubMed  Google Scholar 

  10. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774–800.

    Article  PubMed  CAS  Google Scholar 

  11. Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocr Rev 1999;20:535–82.

    Article  PubMed  CAS  Google Scholar 

  12. Dunaif A, Graf M. Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 1989;83:23–9.

    Article  PubMed  CAS  Google Scholar 

  13. Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endo­crinol Metab 1991;72:83–9.

    Article  CAS  Google Scholar 

  14. Richardson MR. Current perspectives in polycystic ovary syndrome. Am Fam Physician 2003;68:697–704.

    PubMed  Google Scholar 

  15. Barbieri RL, Smith S, Ryan KJ. The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism. Fertil Steril 1988;50:197–212.

    PubMed  CAS  Google Scholar 

  16. Nahum R, Thong KJ, Hillier SG. Metabolic regulation of androgen production by human thecal cells in vitro. Hum Reprod 1995;10:75–81.

    Article  PubMed  CAS  Google Scholar 

  17. Prelevic GM, Wurzburger MI, Balint-Peric L. LH pulsatility and response to a single s.c. injection of buserelin in polycystic ovary syndrome. Gynecol Endocrinol 1990;4:1–13.

    Article  PubMed  CAS  Google Scholar 

  18. Bergh C, Carlsson B, Olsson JH, Selleskog U, Hillensjo T. Regulation of androgen production in cultured human thecal cells by insulin-like growth factor I and insulin. Fertil Steril 1993;59:323–31.

    PubMed  CAS  Google Scholar 

  19. Willis D, Franks S. Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. J Clin Endocrinol Metab 1995;80:3788–90.

    Article  PubMed  CAS  Google Scholar 

  20. Escobar-Morreale HF, Luque-Ramirez M, San Millan JL. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev 2005;26:251–82.

    Article  PubMed  CAS  Google Scholar 

  21. Nelson VL, Qin KN, Rosenfield RL, Wood JR, Penning TM, Legro RS, et al. The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2001;86:5925–33.

    Article  PubMed  CAS  Google Scholar 

  22. Azziz R. Androgen excess is the key element in polycystic ovary syndrome. Fertil Steril 2003;80:252–4.

    Article  PubMed  Google Scholar 

  23. Ibanez L, Valls C, Ferrer A, Ong K, Dunger DB, De Zegher F. Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. J Clin Endocrinol Metab 2002;87:2870–4.

    Article  PubMed  CAS  Google Scholar 

  24. Harborne L, Fleming R, Lyall H, Norman J, Sattar N. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet 2003;361:1894–901.

    Article  PubMed  CAS  Google Scholar 

  25. Haas DA, Carr BR, Attia GR. Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome. Fertil Steril 2003; 79:469–81.

    Article  PubMed  Google Scholar 

  26. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647–54.

    Article  PubMed  CAS  Google Scholar 

  27. Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327:951–3.

    Article  PubMed  CAS  Google Scholar 

  28. Elizur SE, Tulandi T. Drugs in infertility and fetal safety. Fertil Steril 2008;89:1595–602.

    Article  PubMed  CAS  Google Scholar 

  29. Ben-Haroush A, Yogev Y, Fisch B. Insulin resistance and metformin in polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2004;115:125–33.

    Article  PubMed  CAS  Google Scholar 

  30. Ortega-Gonzalez C, Luna S, Hernandez L, Crespo G, Aguayo P, Arteaga-Troncoso G, et al. Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:1360–5.

    Article  PubMed  CAS  Google Scholar 

  31. Pirwany IR, Yates RW, Cameron IT, Fleming R. Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea. Hum Reprod 1999;14:2963–8.

    Article  PubMed  CAS  Google Scholar 

  32. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334: 574–9.

    Article  PubMed  CAS  Google Scholar 

  33. Patane G, Piro S, Rabuazzo AM, Anello M, Vigneri R, Purrello F. Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta-cells. Diabetes 2000; 49:735–40.

    Article  PubMed  Google Scholar 

  34. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002;137:25–33.

    PubMed  CAS  Google Scholar 

  35. Attia GR, Rainey WE, Carr BR. Metformin directly inhibits androgen production in human thecal cells. Fertil Steril 2001;76:517–24.

    Article  PubMed  CAS  Google Scholar 

  36. Adashi EY, Resnick CE, D’Ercole AJ, Svoboda ME, Van Wyk JJ. Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocr Rev 1985;6:400–20.

    Article  PubMed  CAS  Google Scholar 

  37. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992;36: 105–11.

    Article  CAS  Google Scholar 

  38. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.

    Article  PubMed  CAS  Google Scholar 

  39. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71.

    Article  PubMed  CAS  Google Scholar 

  40. Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab 2002;87:569–74.

    Article  PubMed  CAS  Google Scholar 

  41. Costello MF, Shrestha B, Eden J, Johnson NP, Sjoblom P. Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review. Hum Reprod 2007;22:1200–9.

    Article  PubMed  CAS  Google Scholar 

  42. Vessey M, Painter R. Oral contraceptive use and cancer. Findings in a large cohort study, 1968–2004. Br J Cancer 2006;95:385–9.

    Article  PubMed  CAS  Google Scholar 

  43. Schlesselman JJ. Risk of endometrial cancer in relation to use of combined oral contraceptives. A practitioner’s guide to meta-analysis. Hum Reprod 1997;12:1851–63.

    Article  PubMed  CAS  Google Scholar 

  44. Cosma M, Swiglo BA, Flynn DN, Kurtz DM, Labella ML, Mullan RJ, et al. Clinical review: insulin sensitizers for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J Clin Endocrinol Metab 2008;93:1135–42.

    Article  PubMed  CAS  Google Scholar 

  45. Martin KA, Chang RJ, Ehrmann DA, Ibanez L, Lobo RA, Rosenfield RL, et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93:1105–20.

    Article  PubMed  CAS  Google Scholar 

  46. Godsland IF, Walton C, Felton C, Proudler A, Patel A, Wynn V. Insulin resistance, secretion, and metabolism in users of oral contraceptives. J Clin Endocrinol Metab 1992;74:64–70.

    Article  PubMed  CAS  Google Scholar 

  47. Diamanti-Kandarakis E, Baillargeon JP, Iuorno MJ, Jakubowicz DJ, Nestler JE. A modern medical quandary: polycystic ovary syndrome, insulin resistance, and oral contraceptive pills. J Clin Endocrinol Metab 2003;88:1927–32.

    Article  PubMed  CAS  Google Scholar 

  48. Vrbikova J, Cibula D. Combined oral contraceptives in the treatment of polycystic ovary syndrome. Hum Reprod Update 2005;11:277–91.

    Article  PubMed  CAS  Google Scholar 

  49. Gilling-Smith C, Willis DS, Beard RW, Franks S. Hypersec­re­tion of androstenedione by isolated thecal cells from polycystic ­ovaries. J Clin Endocrinol Metab 1994;79:1158–65.

    Article  PubMed  CAS  Google Scholar 

  50. Gilling-Smith C, Story H, Rogers V, Franks S. Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1997;47:93–9.

    Article  CAS  Google Scholar 

  51. Wickenheisser JK, Quinn PG, Nelson VL, Legro RS, Strauss JFIII, McAllister JM. Differential activity of the cytochrome P450 17alpha-hydroxylase and steroidogenic acute regulatory protein gene promoters in normal and polycystic ovary syndrome theca cells. J Clin Endocrinol Metab 2000;85:2304–11.

    Article  PubMed  CAS  Google Scholar 

  52. Fujiwara T, Sidis Y, Welt C, Lambert-Messerlian G, Fox J, Taylor A, et al. Dynamics of inhibin subunit and follistatin mRNA during development of normal and polycystic ovary syndrome follicles. J Clin Endocrinol Metab 2001;86:4206–15.

    Article  PubMed  CAS  Google Scholar 

  53. Laven JS, Imani B, Eijkemans MJ, Fauser BC. New approach to polycystic ovary syndrome and other forms of anovulatory infertility. Obstet Gynecol Surv 2002;57:755–67.

    Article  PubMed  Google Scholar 

  54. Costello MF, Eden JA. A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertil Steril 2003;79:1–13.

    Article  PubMed  Google Scholar 

  55. Macgregor AH, Johnson JE, Bunde CA. Further clinical experience with clomiphene citrate. Fertil Steril 1968;19: 616–22.

    PubMed  CAS  Google Scholar 

  56. Randall JM, Templeton A. Cervical mucus score and in vitro sperm mucus interaction in spontaneous and clomiphene citrate cycles. Fertil Steril 1991;56:465–8.

    PubMed  CAS  Google Scholar 

  57. Nakamura Y, Ono M, Yoshida Y, Sugino N, Ueda K, Kato H. Effects of clomiphene citrate on the endometrial thickness and echogenic pattern of the endometrium. Fertil Steril 1997;67:256–60.

    Article  PubMed  CAS  Google Scholar 

  58. Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997;3:359–65.

    Article  PubMed  CAS  Google Scholar 

  59. Eijkemans MJ, Imani B, Mulders AG, Habbema JD, Fauser BC. High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2). Hum Reprod 2003;18:2357–62.

    Article  PubMed  Google Scholar 

  60. Tulandi T, McInnes RA, Arronet GH. Ovarian hyperstimulation syndrome following ovulation induction with human menopausal gonadotropin. Int J Fertil 1984;29:113–7.

    PubMed  CAS  Google Scholar 

  61. Child TJ, Abdul-Jalil AK, Gulekli B, Tan SL. In vitro maturation and fertilization of oocytes from unstimulated normal ovaries, polycystic ovaries, and women with polycystic ovary syndrome. Fertil Steril 2001;76:936–42.

    Article  PubMed  CAS  Google Scholar 

  62. Chian RC, Buckett WM, Tulandi T, Tan SL. Prospective randomized study of human chorionic gonadotrophin priming before immature oocyte retrieval from unstimulated women with polycystic ovarian syndrome. Hum Reprod 2000;15:165–70.

    Article  PubMed  CAS  Google Scholar 

  63. Nestler JE, Strauss JFIII. Insulin as an effector of human ovarian and adrenal steroid metabolism. Endocrinol Metab Clin North Am 1991;20:807–23.

    PubMed  CAS  Google Scholar 

  64. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876–80.

    Article  PubMed  CAS  Google Scholar 

  65. Creanga AA, Bradley HM, McCormick C, Witkop CT. Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstet Gynecol 2008;111:959–68.

    Article  PubMed  CAS  Google Scholar 

  66. Moll E, van der Veen F, van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update 2007;13:527–37.

    Article  PubMed  CAS  Google Scholar 

  67. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–66.

    Article  PubMed  CAS  Google Scholar 

  68. Cataldo NA, Barnhart HX, Legro RS, Myers ER, Schlaff WD, Carr BR et al. Extended-release metformin does not reduce the clomiphene citrate dose required to induce ovulation in polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:3124–7.

    Article  PubMed  CAS  Google Scholar 

  69. Sills ES, Perloe M, Palermo GD. Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and reproductive outcomes. Eur J Obstet Gynecol Reprod Biol 2000;91:135–41.

    Article  PubMed  CAS  Google Scholar 

  70. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:524–9.

    Article  PubMed  CAS  Google Scholar 

  71. Spiller HA, Sawyer TS. Toxicology of oral antidiabetic medications. Am J Health Syst Pharm 2006;63:929–38.

    Article  PubMed  CAS  Google Scholar 

  72. Gan SC, Barr J, Arieff AI, Pearl RG. Biguanide-associated lactic acidosis. Case report and review of the literature. Arch Intern Med 1992;152:2333–6.

    Article  PubMed  CAS  Google Scholar 

  73. Huckabee WE. Lactic Acidosis. Am J Cardiol 1963;12:663–6.

    Article  PubMed  CAS  Google Scholar 

  74. Tucker GT, Casey C, Phillips PJ, Connor H, Ward JD, Woods HF. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol 1981;12:235–46.

    PubMed  CAS  Google Scholar 

  75. Ficicioglu C, Api M, Ozden S. The number of follicles and ovarian volume in the assessment of response to clomiphene citrate treatment in polycystic ovarian syndrome. Acta Obstet Gynecol Scand 1996;75:917–21.

    Article  PubMed  CAS  Google Scholar 

  76. Adrogue HJ. Metabolic acidosis: pathophysiology, diagnosis and management. J Nephrol 2006;19 Suppl 9:S62–9.

    Google Scholar 

  77. Heaney D, Majid A, Junor B. Bicarbonate haemodialysis as a treatment of metformin overdose. Nephrol Dial Transplant 1997;12:1046–7.

    Article  PubMed  CAS  Google Scholar 

  78. Luft FC. Lactic acidosis update for critical care clinicians. J Am Soc Nephrol 2001;12 Suppl 17:S15–9.

    Google Scholar 

  79. Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease. Semin Dial 2004;17:365–70.

    Article  PubMed  Google Scholar 

  80. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 1995;333:541–9.

    Article  PubMed  CAS  Google Scholar 

  81. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997;103:491–7.

    Article  PubMed  CAS  Google Scholar 

  82. Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T. Effects of troglitazone: a new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 1996;19:151–6.

    Article  PubMed  CAS  Google Scholar 

  83. Wojcicki J, Szwed G, Drozdowska-Ksiazek D. The antitussive and expectorant drug Duopect evaluated by the preferential test. Arch Immunol Ther Exp (Warsz) 1976;24:549–52.

    CAS  Google Scholar 

  84. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004;351:1106–18.

    Article  PubMed  Google Scholar 

  85. Mitwally MF, Kuscu NK, Yalcinkaya TM. High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome. Hum Reprod 1999;14:2700–3.

    Article  PubMed  CAS  Google Scholar 

  86. Baillargeon JP, Iuorno MJ, Nestler JE. Insulin sensitizers for polycystic ovary syndrome. Clin Obstet Gynecol 2003;46:325–40.

    Article  PubMed  Google Scholar 

  87. Ehrmann DA, Rychlik D. Pharmacologic treatment of polycystic ovary syndrome. Semin Reprod Med 2003;21:277–83.

    Article  PubMed  CAS  Google Scholar 

  88. Campbell RK, White JRJr., Saulie BA. Metformin: a new oral biguanide. Clin Ther 1996;18:360–71; discussion 59.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Texas at Southwestern Medical Center, Department of OB/GYN,, Division of Reproductive Endocrinology & Infertility, 5323 Harry Hines Blvd., Dallas, TX, 75390-9032, USA

    Satin S. Patel, Victor E. Beshay & Bruce R. Carr

Authors
  1. Satin S. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Victor E. Beshay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruce R. Carr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruce R. Carr .

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    Patel, S.S., Beshay, V.E., Carr, B.R. (2009). Metformin for the Treatment of Polycystic Ovary Syndrome (PCOS). In: Voorhis, B., Schlegel, P., Racowsky, C., Carrell, D. (eds) Biennial Review of Infertility. Humana Press. https://doi.org/10.1007/978-1-60327-392-3_2

    Download citation

    • DOI: https://doi.org/10.1007/978-1-60327-392-3_2

    • Published:

    • Publisher Name: Humana Press

    • Print ISBN: 978-1-60327-391-6

    • Online ISBN: 978-1-60327-392-3

    • eBook Packages: MedicineMedicine (R0)

    Publish with us

    Policies and ethics

    Search

    Navigation