Cancer Causes & Control

, Volume 17, Issue 4, pp 577–582 | Cite as

Circulating Melatonin Levels: Possible Link Between Parkinson’s Disease and Cancer Risk?

  • Eva Schernhammer
  • Honglei Chen
  • Beate Ritz
Special Section on Cancer and Rhythm Original Paper


Lower rates of cancer mortality/incidence in patients with Parkinson’s disease (PD) have given rise to speculations about risk or preventative factors common to both diseases, including life-style factors (such as smoking) and genetic susceptibility. Melatonin, a hormone known for its sleep regulatory effects, may play an important role in carcinogenesis as suggested by substantial laboratory and less direct epidemiologic evidence. Particularly, a reduction in melatonin, such as experienced by persons who are exposed to light at night, appears to increase cancer risk. Variations in melatonin levels have been linked to PD in several different ways. Some studies show higher morning melatonin levels in PD patients than in healthy controls. One could speculate that the sleep disorders that affect almost two thirds of those suffering from PD and can precede PD motor symptoms by several years may be associated with variations in melatonin levels. Moreover, in animal models, interventions that increase the bioavailability of melatonin appears to increase the severity of parkinsonian symptoms, whereas reduction in melatonin by pinealectomy or exposure to bright light can enhance recovery from parkinsonisms symptoms. Finally, preliminary epidemiological evidence suggests that longer years of working night shifts is associated with a reduced risk of PD among participants of the Nurses’ Health Study (NHS), whereas longer hours of sleep appear to increase their risk. In sum, while lower melatonin concentrations may predict a higher cancer risk, there is also some evidence that they may be associated with a lower risk of PD. We therefore hypothesize that elevated circulating melatonin levels in PD patients may contribute to their lower cancer rates.


Melatonin Cancer Parkinson’s disease 


  1. 1.
    Barbeau A, KJoly JG (1963) Parkinsonism et cancer. Union Med Can 92:169–174PubMedGoogle Scholar
  2. 2.
    Ben-Shlomo Y, Marmot MG (1995) Survival and cause of death in a cohort of patients with parkinsonism: possible clues to aetiology? J Neurol Neurosurg Psychiatry 58:293–299PubMedGoogle Scholar
  3. 3.
    Gorell JM, Johnson CC, Rybicki BA (1994) Parkinson’s disease and its comorbid disorders: an analysis of Michigan mortality data, 1970 to 1990. Neurology 44:1865–1868PubMedGoogle Scholar
  4. 4.
    Harada H, Nishikawa S, Takahashi K (1983) Epidemiology of Parkinson’s disease in a Japanese city. Arch Neurol 40:151–154PubMedGoogle Scholar
  5. 5.
    Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression, and mortality. 1967.Neurology 57:S11–S26Google Scholar
  6. 6.
    Jansson B, Jankovic J (1985) Low cancer rates among patients with Parkinson’s disease. Ann Neurol 17:505–509CrossRefPubMedGoogle Scholar
  7. 7.
    Pritchard PBr, Netsky MG (1973) Prevalence of neoplasms and causes of death in paralysis agitans. A necropsy study.Neurology 23:215–222PubMedGoogle Scholar
  8. 8.
    Rajput AH, Offord KP, Beard CM, Kurland LT (1987) A case-control study of smoking habits, dementia, and other illnesses in idiopathic Parkinson’s disease. Neurology 37:226–232PubMedGoogle Scholar
  9. 9.
    Westlund K (1956) Cancer as a cause of death among patients with other chronic diseases. JAMA 162:1003Google Scholar
  10. 10.
    Minami Y, Yamamoto R, Nishikouri M, Fukao A, Hisamichi S (2000) Mortality and cancer incidence in patients with Parkinson’s disease.J Neurol 247:429–434CrossRefPubMedGoogle Scholar
  11. 11.
    Elbaz A, Peterson BJ, Yang P, et al. (2002) Nonfatal cancer preceding Parkinson’s disease: a case-control study. Epidemiology 13:157–164CrossRefPubMedGoogle Scholar
  12. 12.
    Rostami-Hodjegan ALM, Woods HF, Tucker GT (1998) Meta-analysis of studies of the CYP2D6 polymorphism in relation to lung cancer and Parkinson’s disease. Pharmacogenetics 8:227–238PubMedGoogle Scholar
  13. 13.
    Morens DM GA, Davis JW, Ross GW, White LR, Reed D (1996) Evidence against the operation of selective mortality in explaining the association between cigarette smoking and reduced occurrence of idiopathic Parkinson disease.Am J Epidemiol 144:400–404PubMedGoogle Scholar
  14. 14.
    Elbaz A, Bower JH, Peterson BJ, et al. (2003) Survival study of Parkinson disease in Olmsted County, Minnesota. Arch Neurol 60:91–96PubMedGoogle Scholar
  15. 15.
    Vanacore N, Spila-Alegiani S, Raschetti R, Meco G (1999) Mortality cancer risk in parkinsonian patients: a population-based study.Neurology 52:395–398PubMedGoogle Scholar
  16. 16.
    Olsen JH, Friis S, Frederiksen K, McLaughlin JK, Mellemkjaer L, Moller H (2005) Atypical cancer pattern in patients with Parkinson’s disease. Br J Cancer 92:201–205CrossRefPubMedGoogle Scholar
  17. 17.
    Jenner P (1998) Oxidative mechanisms in nigral cell death in Parkinson’s disease. Mov Disord 13:24–34PubMedGoogle Scholar
  18. 18.
    Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53:S26–S36CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang SM, Hernan MA, Chen H, Spiegelman D, Willett WC, Ascherio A (2002) Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk. Neurology 59:1161–1169PubMedGoogle Scholar
  20. 20.
    Leon J, Acuna-Castroviejo D, Sainz RM, Mayo JC, Tan DX, Reiter RJ (2004) Melatonin and mitochondrial function. Life Sci 75:765–790CrossRefPubMedGoogle Scholar
  21. 21.
    Mayo JC, Sainz RM, Uria H, Antolin I, Esteban MM, Rodriguez C (1998) Melatonin prevents apoptosis induced by 6-hydroxydopamine in neuronal cells: implications for Parkinson’s disease.J Pineal Res 24:179–192PubMedGoogle Scholar
  22. 22.
    Reiter RJ, Guerrero JM, Escames G, Pappolla MA, Acuna-Castroviejo D (1997) Prophylactic actions of melatonin in oxidative neurotoxicity. Ann N Y Acad Sci 825:70–78PubMedGoogle Scholar
  23. 23.
    Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z (2003) Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 50:1129–1146PubMedGoogle Scholar
  24. 24.
    Absi E, Ayala A, Machado A, Parrado J (2000) Protective effect of melatonin against the 1-methyl−4-phenylpyridinium-induced inhibition of complex I of the mitochondrial respiratory chain. J Pineal Res 29:40–47CrossRefPubMedGoogle Scholar
  25. 25.
    Dabbeni-Sala F, Di Santo S, Franceschini D, Skaper SD, Giusti P (2001) Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity. FASEB J 15:164–170CrossRefPubMedGoogle Scholar
  26. 26.
    Khaldy H, Escames G, Leon J, Vives F, Luna JD, Acuna-Castroviejo D (2000) Comparative effects of melatonin, L-deprenyl, Trolox and ascorbate in the suppression of hydroxyl radical formation during dopamine autoxidation in vitro. J Pineal Res 29:100–107CrossRefPubMedGoogle Scholar
  27. 27.
    Acuna-Castroviejo D, Coto-Montes A, Gaia Monti M, Ortiz GG, Reiter RJ (1997) Melatonin is protective against MPTP-induced striatal and hippocampal lesions. Life Sci 60:PL23–PL29PubMedGoogle Scholar
  28. 28.
    Antolin I, Mayo JC, Sainz RM, et al. (2002) Protective effect of melatonin in a chronic experimental model of Parkinson’s disease. Brain Res 943:163–173PubMedGoogle Scholar
  29. 29.
    Coulom H, Birman S (2004) Chronic exposure to rotenone models sporadic Parkinson’s disease in Drosophila melanogaster. J Neurosci 24:10993–10998CrossRefPubMedGoogle Scholar
  30. 30.
    Jin BK, Shin DY, Jeong MY, et al. (1998) Melatonin protects nigral dopaminergic neurons from 1-methyl−4-phenylpyridinium (MPP+) neurotoxicity in rats. Neurosci Lett 245:61–64CrossRefPubMedGoogle Scholar
  31. 31.
    Thomas B, Mohanakumar KP (2004) Melatonin protects against oxidative stress caused by 1-methyl−4-phenyl−1,2,3,6-tetrahydropyridine in the mouse nigrostriatum. J Pineal Res 36:25–32CrossRefPubMedGoogle Scholar
  32. 32.
    Morgan WW, Nelson JF (2001) Chronic administration of pharmacological levels of melatonin does not ameliorate the MPTP-induced degeneration of the nigrostriatal pathway.Brain Res 921:115–121CrossRefPubMedGoogle Scholar
  33. 33.
    van der Schyf CJ, Castagnoli K, Palmer S, Hazelwood L, Castagnoli NJ (2000) Melatonin fails to protect against long-term MPTP-induced dopamine depletion in mouse striatum.Neurotox Res 1:261–269PubMedGoogle Scholar
  34. 34.
    Willis GL, Armstrong SM (1999) A therapeutic role for melatonin antagonism in experimental models of Parkinson’s disease. Physiol Behav 66:786–795CrossRefGoogle Scholar
  35. 35.
    Catala MD, Canete-Nicolas C, Iradi A, Tarazona PJ, Tormos JM, Pascual-Leone A (1997) Melatonin levels in Parkinson’s disease: drug therapy versus electrical stimulation of the internal globus pallidus. Exp Gerontol 32:553–558PubMedGoogle Scholar
  36. 36.
    Willis GL, Armstrong SM (1999) A therapeutic role for melatonin antagonism in experimental models of Parkinson’s disease.Physiol Behav 66:785–795CrossRefPubMedGoogle Scholar
  37. 37.
    Zisapel N (2001) Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting. Cell Mol Neurobiol 21:605–616CrossRefPubMedGoogle Scholar
  38. 38.
    Cos S, Fernandez F, Sanchez-Barcelo EJ (1996) Melatonin inhibits DNA synthesis in MCF−7 human breast cancer cells in vitro. Life Sci 58:2447–2453PubMedGoogle Scholar
  39. 39.
    Cos S, Fernandez R, Guezmes A, Sanchez-Barcelo EJ (1998) Influence of melatonin on invasive and metastatic properties of MCF−7 human breast cancer cells. Cancer Res 58:4383–4390PubMedGoogle Scholar
  40. 40.
    Cos S, Mediavilla MD, Fernandez R, Gonzalez-Lamuno D, Sanchez-Barcelo EJ (2002) Does melatonin induce apoptosis in MCF−7 human breast cancer cells in vitro? J Pineal Res 32:90–96CrossRefPubMedGoogle Scholar
  41. 41.
    Hill SM, Blask DE (1988) Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF−7) in culture. Cancer Res 48:6121–6126PubMedGoogle Scholar
  42. 42.
    Kanishi Y, Kobayashi Y, Noda S, Ishizuka B, Saito K (2000) Differential growth inhibitory effect of melatonin on two endometrial cancer cell lines. J Pineal Res 28:227–233CrossRefPubMedGoogle Scholar
  43. 43.
    Mediavilla MD, Cos S, Sanchez-Barcelo EJ (1999) Melatonin increases p53 and p21WAF1 expression in MCF−7 human breast cancer cells in vitro. Life Sci 65:415–420CrossRefPubMedGoogle Scholar
  44. 44.
    Petranka J, Baldwin WS, Bierman J, Jayadev S, Barrett JC, Murphy E (1999) The oncostatic action of melatonin in an ovarian carcinoma cell line. Pineal Res 26:129–136Google Scholar
  45. 45.
    Shiu SY, Li L, Xu JN, Pang CS, Wong JT, Pang SF (1999) Melatonin-induced inhibition of proliferation and G1/S cell cycle transition delay of human choriocarcinoma JAr cells: possible involvement of MT2 (MEL1B) receptor. Pineal Res 27:183–192Google Scholar
  46. 46.
    Sze SF, Ng TB, Liu WK (1993) Antiproliferative effect of pineal indoles on cultured tumor cell lines. J Pineal Res 14:27–33PubMedGoogle Scholar
  47. 47.
    Ying SW, Niles LP, Crocker C (1993) Human malignant melanoma cells express high-affinity receptors for melatonin: antiproliferative effects of melatonin and 6-chloromelatonin. Eur J Pharmacol 246:89–96PubMedGoogle Scholar
  48. 48.
    Tamarkin L, Cohen M, Roselle D, Reichert C, Lippman M, Chabner B (1981) Melatonin inhibition and pinealectomy enhancement of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in the rat. Cancer Res 41:4432–4436PubMedGoogle Scholar
  49. 49.
    Musatov SA, Anisimov VN, Andre V, Vigreux C, Godard T, Sichel F (1999) Effects of melatonin on N-nitroso-N-methylurea-induced carcinogenesis in rats and mutagenesis in vitro (Ames test and COMET assay).Cancer Lett 138:37–44CrossRefPubMedGoogle Scholar
  50. 50.
    Anisimov VN, Popovich IG, Zabezhinski MA (1997) Melatonin and colon carcinogenesis: I. Inhibitory effect of melatonin on development of intestinal tumors induced by 1,2-dimethylhydrazine in rats. Carcinogenesis 18:1549–1553CrossRefPubMedGoogle Scholar
  51. 51.
    Anisimov VN, Kvetnoy IM, Chumakova NK, et al. (1999) Melatonin and colon carcinogenesis. Exp Toxicol Pathol 51:47–52PubMedGoogle Scholar
  52. 52.
    Cini G, Coronnello M, Mini E, Neri B (1998) Melatonin’s growth-inhibitory effect on hepatoma AH 130 in the rat. Cancer Lett 125:51–59CrossRefPubMedGoogle Scholar
  53. 53.
    Mocchegiani E, Perissin L, Santarelli L, et al. (1999) Melatonin administration in tumor-bearing mice (intact and pinealectomized) in relation to stress, zinc, thymulin and IL−2. Int J Immunopharmacol 21:27–46PubMedGoogle Scholar
  54. 54.
    Brzezinski A (1997) Melatonin in humans. N Engl J Med 336:186–195CrossRefPubMedGoogle Scholar
  55. 55.
    Blask DE, Dauchy RT, Sauer LA, Krause JA, Brainard GC (2002) Light during darkness, melatonin suppression and cancer progression. Neuroendocrinol Lett 23:52–56PubMedGoogle Scholar
  56. 56.
    Dauchy RT, Blask DE, Sauer LA, Brainard GC, Krause JA (1999) Dim light during darkness stimulates tumor progression by enhancing tumor fatty acid uptake and metabolism. Cancer Letters 144:131–136CrossRefPubMedGoogle Scholar
  57. 57.
    Vijayalaxmi, Thomas CRJ, Reiter RJ, Herman TS (2002) Melatonin: from basic research to cancer treatment clinics. J Clin Oncol 20:2575–2601CrossRefPubMedGoogle Scholar
  58. 58.
    Schernhammer ES, Hankinson SE (2003) Light at night: a novel risk factor for cancer in shift workers? Clin Occupational Environment Med 3:263–278Google Scholar
  59. 59.
    Snyder SH, Axelrod J, Zweig M (1967) Circadian rhythm in the serotonin content of the rat pineal gland: regulating factors. J Pharmacol Exp Ther 158:206–213PubMedGoogle Scholar
  60. 60.
    Zeitzer JM, Dijk DJ, Kronauer R, Czeisler C (2000) Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression. J Physiol 526:695–702PubMedGoogle Scholar
  61. 61.
    Graham C, Cook MR (2001) Examination of the melatonin hypothesis in women exposed at night to EMF or bright light. Environ Health Perspect 109:501–507PubMedGoogle Scholar
  62. 62.
    Davis S, Mirick DK, Stevens RG (2001) Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 93:1557–1562PubMedGoogle Scholar
  63. 63.
    Hansen J (2001) Increased breast cancer risk among women who work predominantly at night. Epidemiology 12:74–77CrossRefPubMedGoogle Scholar
  64. 64.
    Pukkala E, Auvinen H, Wahlberg G (1995) Incidence of cancer among Finnish airline cabin attendants. BMJ 311:649–652PubMedGoogle Scholar
  65. 65.
    Rafnsson V, Tulinius H, Jonasson JG, Hrafnkelsson J (2001) Risk of breast cancer in female flight attendants: a population-based study (Iceland). Cancer Causes and Control 12:95–101Google Scholar
  66. 66.
    Schernhammer ES, Laden F, Speizer FE, et al. (2001) Rotating night shifts and risk of breast cancer in women participating in the Nurses’ Health Study. J Natl Cancer Inst 93:1563–1568PubMedGoogle Scholar
  67. 67.
    Tynes T, Hannevik M, Andersen A, Vistnes A, Haldorsen T (1996) Incidence of breast cancer in Norwegian female radio and telegraph operators. Cancer Cause Control 7:197–204CrossRefGoogle Scholar
  68. 68.
    Ballard T, Lagorio S, De Angelis G, Verdecchia A (2000) Cancer incidence and mortality among flight personnel: a meta-analysis. Aviat Space Environ Med 71:216–224PubMedGoogle Scholar
  69. 69.
    Mawson AR (1998) Breast cancer in female flight attendants.Lancet 352:626PubMedGoogle Scholar
  70. 70.
    Whelan EA (2003) Cancer incidence in airline cabin crew. Occup Environ Med 60:805–806PubMedGoogle Scholar
  71. 71.
    Schernhammer E, Kroenke C, Laden F, Hankinson S (2005) Night work and melatonin levels in women participating in the Nurses’ Health Study II: Associate with breast cancer risk. In: 2nd Symposium of the Dana-Farber/Harvard Cancer Center Program in Breast Cancer, 2005, BostonGoogle Scholar
  72. 72.
    Moller H, Mellemkjaer L, McLaughlin JK, Olsen JH (1995) Occurrence of different cancers in patients with Parkinson’s disease. BMJ 310:1500–1501PubMedGoogle Scholar
  73. 73.
    Anton-Tay F, Diaz JL, Fernandez-Guardiola A (1971) On the effect of melatonin upon human brain. Its possible therapeutic implications. Life Sci I 10:841–850PubMedGoogle Scholar
  74. 74.
    Fertl E, Auff E, Doppelbauer A, Waldhauser F (1991) Circadian secretion pattern of melatonin in Parkinson’s disease. J Neural Transm Park Dis Dement Sect 3:41–47CrossRefPubMedGoogle Scholar
  75. 75.
    Struppler A, Velbo-Groneberg P, Claussen M (1976) Clinic and pathophysiology of tremor In: Birkmayer W, Hornykiewicz O, (eds) Advances in Parkinsonism. Editions Roche, Basel, pp 287Google Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  1. 1.Department of MedicineChanning LaboratoryBrigham
  2. 2.Women’s Hospital and Harvard Medical SchoolBostonUSA
  3. 3.LBI-ACR Vienna & ACR-ITR ViennaAustria
  4. 4.Department of NutritionHarvard School of Public HealthBostonUSA
  5. 5.Department of Epidemiology and Environmental HealthUCLA School of Public HealthLos AngelesUSA
  6. 6.Department of NeurologyUCLA School of MedicineLos AngelesUSA

Personalised recommendations