1. health and fitness
2. aging

Melatonin treatment of aging woman: doses, side effects, how to
manage them.
th
EMAA Friday October 17 , 2008
Melatonin decreases dramatically with aging compare with the optimal value of the young adult at the age
of thirty. It remains only 50% at forty years and then years later the plasma levels are even lower of 75%. At
60 years melatonin level represents 9% of the young adult and there may be no increase in melatonin
production at night (1, 2).
The signs of over dosage during melatonin therapy are: tachycardia, sweating events, heavy head in the
morning, too vivid dreams, those might be assigned to excess stimulation of the 5’ deiodinase activity which
converts T4, the inactive form, into T3 the powerful form of thyroid hormones (3, 4, 5).
Another side effect is a deep prolonged sleepiness the whole night until late in the morning. All those side
effects may be solved by reducing melatonin dosage. In case of insufficient daylight exposure during the day
(too dark office room or insufficient lighthouse or during autumn and wintertime) melatonin receptor will be
less synthesized but also endogenous melatonin secretion at night will be decreased as of an excess of light
in bedroom at night may produce the same adverse effects (6, 7, 8, 9, 10) . Stress or excess cortisol (11) and
adrenaline are responsible for a decrease in melatonin secretion so that melatonin dosage should be
increased. Exposure to magnetic fields is associated with decreased nocturnal melatonin levels. Many
medicines may interfere with melatonin production (12, 13, 14) : B-blocking agents (15, 16), benzodiazepine
(17, 18), glucocorticoids, oral contraceptive pill (19), sodium valproate, all those agents decrease melatonin
production. Alcohol (20), as tobacco (21, 22) consumption decrease melatonin levels during the night.
Caffeine, ingested in the evening at a dose corresponding to two ordinary cups of coffee, augments the
nocturnal serum melatonin level, which supports the notion that cytochrome P450(CYP)1A2 is involved in
the hepatic metabolism of human melatonin (23).
Melatonin therapy increasesT4 conversion into T3 and also growyh hormone, DHEA production (24, 25, 26,
27). It has no effect on ovarian function in case of physiological supplementation but may reduce estrogens
levels in case of overdosage or prescribed for postmenopausal women (28)., Melatonin should be avoided
during pregnancy and breast feeding since its teratogenic effect is not known. Patients suffering from autoimmune diseases have been shown to have an imbalance between cortisol and melatonin in favor of this last
one (29). Melatonin supplementation may worsen auto-immune disease (30, 31). Melatonin is an
immunomodulation agent it alters the balance of leucocyte T helper Th1 and Th2 cells mainly towards Th1
response, although, stimulating the production of natural killer cells, monocytes and leucocytes (32, 33, 34,
35, 36).
References
1. Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians. J
Pineal Res. 2004 May;36(4):256-61.
2. Melatonin and aging: prospects for human treatment. Bubenik GA, Konturek SJ. . J Physiol Pharmacol. 2011
Feb;62(1):13-9.
3. Melatonin specifically stimulates type-II thyroxine 5'-deiodination in brown adipose tissue of Syrian hamsters. PuigDomingo M, Guerrero JM, Menéndez-Pelaez A, Reiter RJ. J Endocrinol. 1989 Aug;122(2):553-6.
4. Nocturnal increases in the triiodothyronine/thyroxine ratio in the rat thymus and pineal gland follow increases of type
II 5'-deiodinase activity. Soutto M, Guerrero JM, Osuna C, Molinero P. Int J Biochem Cell Biol. 1998 Feb;30(2):235-41.
5. Evidence for circadian variations of thyroid hormone concentrations and type II 5'-iodothyronine deiodinase activity in
the rat central nervous system. Campos-Barros A, Musa A, Flechner A, Hessenius C, Gaio U, Meinhold H, Baumgartner A.
J Neurochem. 1997 Feb;68(2):795-803.
6. Positive Effect of Daylight Exposure on Nocturnal Urinary Melatonin Excretion in the Elderly: A Cross-Sectional Analysis
of the HEIJO-KYO Study. Kenji Obayashi, Keigo Saeki, Junko Iwamoto, Nozomi Okamoto, Kimiko Tomioka, Satoko Nezu,
Yoshito Ikada and Norio Kurumatani. The Journal of Clinical Endocrinology & Metabolism September 4, 2012 jc.20121873.
7. Benefits of Sunlight: A Bright Spot for Human Health. M. Nathaniel Mead. Environ Health Perspect. 2008 April; 116(4):
A160–A167
8. Neurochemical and Neuropharmacological Aspects of Circadian Disruptions: An Introduction to Asynchronization. Jun
Kohyama. Curr Neuropharmacol. 2011 June; 9(2): 330–341.
9. Night shift work characteristics and 6-sulfatoxymelatonin (MT6s) in rotating night shift nurses and midwives. Beata
Peplonska, Agnieszka Bukowska, Jolanta Gromadzinska, Wojciech Sobala, Edyta Reszka, Jenny-Anne Lie, Helge Kjuus,
Wojciech Wasowicz. Occup Environ Med2012;69:339-346 doi:10.1136/oemed-2011-100273
10. Exposure to Room Light before Bedtime Suppresses Melatonin Onset and Shortens Melatonin Duration in Humans.
Joshua J. Gooley, Kyle Chamberlain, Kurt A. Smith, Sat Bir S. Khalsa, Shantha M. W. Rajaratnam, Eliza Van Reen, Jamie M.
Zeitzer, Charles A. Czeisler and Steven W. Lockley. The Journal of Clinical Endocrinology & Metabolism March 1, 2011 vol.
96 no. 3 E463-E472
11. Decreased melatonin concentration in Cushing's syndrome. Soszyński P, Stowińska-Srzednicka J, Kasperlik-Zatuska A,
Zgliczyński S. Horm Metab Res. 1989 Dec;21(12):673-4.
12. Melatonin and magnetic fields. Karasek M, Lerchl A. Neuro Endocrinol Lett. 2002 Apr;23 Suppl 1:84-7.
13. Effects of an artificial magnetic field on serotonin N-acetyltransferase activity and melatonin content of the rat pineal
gland. Dr. H. A. Welker, P. Semm, R. P. Willig, J. C. Commentz, W. Wiltschko, L. Vollrath. Experimental Brain Research.
May 1983, Volume 50, Issue 2-3, pp 426-432.
14. Reduced Excretion of a Melatonin Metabolite in Workers Exposed to 60 Hz Magnetic Fields. James B. Burch, John S.
Reif, Michael G. Yost, Thomas J. Keefe and Charles A. Pitrat. Am J Epidemiol Vol. 150, No. 1, 1999:27-36.
15. Influence of beta-blockers on melatonin release. K. Stoschitzky, A. Sakotnik, P. Lercher, R. Zweiker, R. Maier, P.
Liebmann, W. Lindner. European Journal of Clinical Pharmacology. April 1999, Volume 55, Issue 2, pp 111-115.
16. Effect of propranolol plus exercise on melatonin and growth hormone levels in children with growth delay. A. MuñozHoyos1, E. Hubber, G. Escames, A. Molina-Carballo, M. Macías, A. Valenzuela-Ruiz, J.M. Fernández-García, D. AcuñaCastroviejo. Journal of Pineal Research Volume 30, Issue 2, pages 75–81, March 2001.
17. Improvement of sleep quality by controlled-release melatonin in benzodiazepine-treated elderly insomniacs.
Garfinkel D, Laudon M, Zisapel N. Arch Gerontol Geriatr. 1997 Mar-Apr;24(2):223-31.
18. Nocturnal Enhancement of Plasma Melatonin Could Be Suppressed by Benzodiazepines in Humans. MICHINORI
KABUTO, IKUO NAMURA, YOUICHI SAITOH. Endocrinologia Japonica. Vol. 33 (1986) No. 3 P 405-414
19. The effect of oral contraceptives on the pharmacokinetics of melatonin in healthy subjects with CYP1A2 g.-163C>A
polymorphism. Hilli J, Korhonen T, Turpeinen M, Hokkanen J, Mattila S, Laine K. J Clin Pharmacol. 2008 Aug;48(8):986-94.
20. Alcohol consumption and urinary concentration of 6-sulfatoxymelatonin in healthy women. Stevens RG, Davis S,
Mirick DK, Kheifets L, Kaune W. Epidemiology. 2000 Nov;11(6):660-5.
21. Influence of cigarette smoking on melatonin levels in man. Ursing C, von Bahr C, Brismar K, Röjdmark S. Eur J Clin
Pharmacol. 2005 May;61(3):197-201. Epub 2005 Apr 12.
22. Urinary 6-sulfatoxymelatonin levels and their correlations with lifestyle factors and steroid hormone levels.
Schernhammer ES, Kroenke CH, Dowsett M, Folkerd E, Hankinson SE. J Pineal Res. 2006 Mar;40(2):116-24.
23. Caffeine raises the serum melatonin level in healthy subjects: an indication of melatonin metabolism by cytochrome
P450(CYP)1A2. Ursing C, Wikner J, Brismar K, Röjdmark S. J Endocrinol Invest. 2003 May;26(5):403-6.
24. Effects of melatonin in perimenopausal and menopausal women: our personal experience. Bellipanni G, DI Marzo F,
Blasi F, Di Marzo A. Ann N Y Acad Sci. 2005 Dec;1057:393-402.
25. Stimulatory effect of melatonin on the 5'-monodeiodinase activity in the liver, kidney, and brown adipose tissue
during the early neonatal period of the rabbit. Brzezińska-Slebodzińska E, Slebodziński AB, Styczyńska E. J Pineal Res.
1998 Apr;24(3):137-41.
26. Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol,
dehydroepiandrosterone sulfate, and somatomedin C in elderly women. Pawlikowski M, Kolomecka M, Wojtczak A,
Karasek M. Neuro Endocrinol Lett. 2002 Apr;23 Suppl 1:17-9.
27. Melatonin Modulates Secretion of Growth Hormone and Prolactin by Trout Pituitary Glands and Cells in Culture. J.
Falcón, L. Besseau, D. Fazzari, J. Attia, P. Gaildrat, M. Beauchaud and G. Boeuf. Endocrinology October 1, 2003 vol. 144
no. 10 4648-4658.
28. Changes in nocturnal melatonin secretion in perimenopausal women: correlation with endogenous estrogen
concentrations. Okatani Y, Morioka N, Wakatsuki A. J Pineal Res. 2000 Mar;28(2):111-8.
29. Does melatonin play a disease-promoting role in rheumatoid arthritis? Georges J.M. Maestroni, Daniel P. Cardinali,
Ana I. Esquifino, S.R. Pandi-Perumal. Journal of Neuroimmunology Volume 158, Issue 1 , Pages 106-111, January 2005.
30. Melatonin treatment does not improve rheumatoid arthritis. Georges J Maestroni, Kati Otsa, and Maurizio Cutolo. Br
J Clin Pharmacol. 2008 May; 65(5): 797–798.
31. Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin. Caroline M Forrest,
Gillian M Mackay, Nicholas Stoy, Trevor W Stone, and L Gail Darlington. Br J Clin Pharmacol. 2007 October; 64(4): 517–
526
32. Circadian rhythms in RA. M Cutolo, B Seriolo, C Craviotto, C Pizzorni, A Sulli. Ann Rheum Dis2003;62:593-596.
33. Immunomodulation by melatonin: its significance for seasonally occurring diseases. Srinivasan V, Spence DW, Trakht
I, Pandi-Perumal SR, Cardinali DP, Maestroni GJ. Neuroimmunomodulation. 2008;15(2):93-101. Epub 2008 Aug 5.
34. Melatonin and the immune system in aging. Cardinali DP, Esquifino AI, Srinivasan V, Pandi-Perumal SR.
Neuroimmunomodulation. 2008;15(4-6):272-8. Epub 2008 Nov 26.
35. Influence of melatonin and its precursor L-tryptophan on Th1 dependent contact hypersensitivity. Majewska M, Zajac
K, Zemelka M, Szczepanik M. J Physiol Pharmacol. 2007 Dec;58 Suppl 6:125-32.
36. Melatonin modulation of lymphocyte proliferation and Th1/Th2 cytokine expression. Eva Kühlwein, Michael Irwin.
Journal of Neuroimmunology Volume 117, Issue 1 , Pages 51-57, 2 July 2001.