The Hidden Side of Melatonin: Why Melatonin Might Be Sabotaging Your Health

Melatonin is the ‘‘Chemical Signal of Darkness’’.  Because the duration of melatonin production is the neurochemical signal for the annual change in night length,¹Wehr TA, Duncan WC Jr, Sher L, Aeschbach D, Schwartz PJ, Turner EH, Postolache TT, Rosenthal NE. A circadian signal of change of season in patients with seasonal affective disorder. Arch Gen Psychiatry. 2001 Dec;58(12):1108-14.^,2Julius Axelrod ,The Pineal Gland: A Neurochemical Transducer.Science184,1341-1348(1974). wearing Blue Blocker glasses increases the duration of the “biological night”. The Pineal Gland translates environmental light information into endocrine signals to many parts of the body via the time messenger melatonin.³Wurtman RJ, Axelrod J, Phillips Ls. (1963). Melatonin synthesis in the pineal gland; control by light. science 142: 1071-1073.

Quick Summary of Melatonin Effects on the Body

• Visible light decreases Melatonin levels.
• Darkness increases Melatonin levels.
  • Blue Blocker Glasses increases Melatonin levels.
• Isolation in Dark Room Increases Melatonin levels.
  • Causing Increased Th17 cytokines provoking immune cells.
  • Th17 is involved in immune and tissue inflammatory responses.
  • Th17 cytokines can also cause tissue pathologies.
  • Th17 cells are heavily implicated in autoimmune diseases.
  • Th17 cells can secreting immune factors, such as IL-10, which causes Anaphylactic Shock.
• Melatonin is produced in multiple organs in the body.
• Naturally occurring Melatonin increases Autoimmune cytokine storms and flairs during the Fall and Winter months.
  • Wearing Blue Blocker Glasses increases the amount of naturally produced Melatonin.
• Melatonin lowers Thyroid Stimulating Hormone (TSH).
• Melatonin Increases Polycystic Ovarian Syndrome (PCOS).
• Melatonin increases the Th1, Th2 immune response response to antibodies.
• Melatonin increases Th17 immune response
• Melatonin increases parasite reproduction.

The amount of blue light in a natural environment varies depending on the time of the day (there is more in the morning) and on the reflecting surface such as snow, grass, water, sand or cement, blue blockers which are cutting all wavelengths below 540 nm are effective in naturalistic condition albeit that proper glasses frame are made to cover all angles.⁴Alexandre Sasseville, Nathalie Paquet, Jean Sévigny, Marc Hébert. Blue blocker glasses impede the capacity of bright light to suppress melatonin production. J. Pineal Res. 2006; 41:73–78  

How does Melatonin Affect the Body

Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. 

Melatonin is primarily thought to be found only in the pineal gland. Melatonin is mainly produced in the pineal gland during the dark phase (night). Its secretion from the pineal gland has been classically associated with circadian and circanual rhythm regulation. However, melatonin production is not confined exclusively to the pineal gland, but other tissues including retina, Harderian glands, gut, ovary, testes, bone marrow, thymus and bone marrow of humans and lens also produce it.⁵Menendez-Pelaez, A.; Howes, K.A.; Gonzalez-Brito, A.; Reiter, R.J. N-acetyltransferase activity, hydroxyindole-Omethyltransferase activity, and melatonin levels in the Harderian glands of the female Syrian hamster: changes during the light:dark cycle and the effect of 6-parachlorophenylalanine administration. Biochem. Biophys. Res. Commun., 1987, 145, 1231-1238.^,6Tan, D.X.; Manchester, L.C.; Reiter, R.J.; Qi, W.B.; Zhang, M.; Weintraub, S.T.; Cabrera, J.; Sainz, R.M.; Mayo, J.C. Identification of highly elevated levels of melatonin in bone marrow: its origin and significance. Biochim. Biophys. Acta., 1999, 1472, 206-214.^,7Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res. 2000 May; 28(4):193-202.^,8Naranjo MC, Guerrero JM, Rubio A, Lardone PJ, Carrillo-Vico A, et. al. Melatonin biosynthesis in the thymus of humans and rats. Cell Mol Life Sci. 2007 Mar; 64(6):781-90.

The gastrointestinal (GI) tract presents another, many times larger, source of melatonin.⁹Jaworek J, Brzozowski T, Konturek SJ. Melatonin as an organoprotector in the stomach and the pancreas. J Pineal Res. 2005 Mar;38(2):73-83. Melatonin stimulates sleep while slowing down GI transit of food so a person in not having bowel movements in the middle of the night.

In addition to marked seasonal changes in reproductive, metabolic, and other physiological functions, many experience seasonal changes in immune function. Increased immune activation in short days is due to the increase in the duration of nightly melatonin secretion acting directly on immune cells to enhance immune responses.¹⁰Drazen DL, Bilu D, Bilbo SD, Nelson RJ. Melatonin enhancement of splenocyte proliferation is attenuated by luzindole, a melatonin receptor antagonist. Am J Physiol Regul Integr Comp Physiol. 2001 May;280(5):R1476-82. 

Melatonin serum levels vary according to the daylight cycle and weather (external ecosystem). Melatonin is also produced by the gut flora and its intestinal concentration is modulated by meals (internal ecosystem). Multiple studies have shown an important effect of melatonin on gastrointestinal function.¹¹Konturek SJ, Konturek PC, Brzozowska I, et al. Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT). J Physiol Pharmacol 2007; 58:381–405.

Melatonin has immune-enhancing effects and can exacerbate autoimmunity. Pinealectomy or light exposure (longer days or night-time light exposure), which suppress melatonin, inhibit T cell autoimmunity. Drugs that inhibit the immunoenhancing effects of melatonin may reduce autoimmune demyelination.¹²Constantinescu CS, Hilliard B, Ventura E, Rostami A. Luzindole, a melatonin receptor antagonist, suppresses experimental autoimmune encephalomyelitis. Pathobiology. 1997;65(4):190-4. Blue Blocker Glass have the opposite effect with immune-enhancing effects, aggravates autoimmunity. 

The Effect of Melatonin on the Ovaries

The concentration of melatonin in human preovulatory follicular fluid is three times more than in the plasma and melatonin and its precursors are found in human ovary extracts.¹³Nakamura Y, Tamura H, Takayama H, Kato H. Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production. Fertil Steril. 2003 Oct;80(4):1012-6.^,14Starr, J. (2011). The Effect of Melatonin on the Ovaries. The Science Journal of the Lander College of Arts and Sciences, 5(1).^,15Tamura H, Nakamura Y, Korkmaz A, Manchester LC, Tan DX, Sugino N, Reiter RJ. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2009 Jul;92(1):328-43. doi: 10.1016/j.fertnstert.2008.05.016. Epub 2008 Sep 18. PMID: 18804205.  Melatonin at high doses is able to suppress human ovulation.¹⁶Olcese JM. Melatonin and Female Reproduction: An Expanding Universe. Front Endocrinol (Lausanne). 2020 Mar 6;11:85. doi: 10.3389/fendo.2020.00085. PMID: 32210911; PMCID: PMC7067698.^,17Voordouw B, Euser R, Verdonk R, Alberda B, deJong F, Drogendijk A, et al. Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation. J Clin Endocrinol Metab. (1992) 74:108–17.^,18Tamura H, Nakamura Y, Korkmaz A, Manchester LC, Tan DX, Sugino N, Reiter RJ. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2009 Jul;92(1):328-43. doi: 10.1016/j.fertnstert.2008.05.016. Epub 2008 Sep 18. PMID: 18804205.

Melatonin in the Ovaries

It is becoming clear that melatonin acts directly on the ovaries.¹⁹Cruz, M.H.; Leal, C.L.; Cruz, J.F.; Tan, D.X.; Reiter, R.J. Essential actions of melatonin in protecting the ovary from oxidative damage. Theriogenology 2014, 82, 925–932. It is known that, compared to other organs, the accumulation of melatonin is highest in the ovaries.²⁰Wurtman, R.J.; Axelrod, J.; Potter, L.T. The uptake of H3-melatonin in endocrine and nervous tissues and the effects of constant light exposure. J. Pharmacol. Exp. Ther. 1964, 143, 314–318. Melatonin also is found at a high concentrations in human follicular fluid, and it increases in proportion to follicular growth.²¹Nakamura, Y.; Tamura, H.; Takayama, H.; Kato, H. Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production. Fertil. Steril. 2003, 80, 1012–1016. Hence, there is a mechanism whereby melatonin is produced in the follicles as they enlarge. Since ovulation is perceived as a phenomenon that resembles inflammation, and as a defense mechanism against ROS generated in follicles, antioxidative enzymes and antioxidants, including melatonin, protect oocytes and granulosa cells from oxidative damage.²²Tamura H, Jozaki M, Tanabe M, Shirafuta Y, Mihara Y, Shinagawa M, Tamura I, Maekawa R, Sato S, Taketani T, Takasaki A, Reiter RJ, Sugino N. Importance of Melatonin in Assisted Reproductive Technology and Ovarian Aging. Int J Mol Sci. 2020 Feb 8;21(3):1135.  

Melatonin and PCOS

Melatonin regulates a variety of physiological and pathophysiological processes including hypothalamic control of circadian rhythms,²³Cassone V.M., Chesworth M.J., Armstrong S.M. Entrainment of rat circadian rhythms by daily injection of melatonin depends upon the hypothalamic suprachiasmatic nuclei. Physiol. Behav. 1986;36:1111–1121.^,24McMillen I.C., Houghton D.C., Young I.R. Melatonin and the development of circadian and seasonal rhythmicity. J. Reprod. Fertil. Suppl. 1995;49:137–146.^,25Cassone VM. Effects of melatonin on vertebrate circadian systems. Trends Neurosci. 1990 Nov;13(11):457-64. regulation of ovulation in women,²⁶Biran V, Decobert F, Bednarek N, Boizeau P, Benoist JF, Claustrat B, Barré J, Colella M, Frérot A, Garnotel R, Graesslin O, Haddad B, Launay JM, Schmitz T, Schroedt J, Virlouvet AL, Guilmin-Crépon S, Yacoubi A, Jacqz-Aigrain E, Gressens P, Alberti C, Baud O. Melatonin Levels in Preterm and Term Infants and Their Mothers. Int J Mol Sci. 2019 Apr 27;20(9):2077.^,27Dollins, A. B., Zhdanova, I. V., Wurtman, R. J., Lynch, H. J., and Deng, M. H. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 1824–1828^,28Batmanabane, M., and Ramesh, K. P. Melatonin Promotes Osteoblast Differentiation and Bone Formation (1996) Anat. Rec. 245, 519–524^,29Esquifino, A. I., Villanua, M. A., and Agrasal, C. Effect of neonatal melatonin administration on sexual development in the rat (1987) J. Steroid Biochem. 27, 1089–1093 and immune system stimulation,³⁰Liebmann PM, Wolfer A, Felsner P, Hofer D, Schauenstein K (1997) Melatonin and the immune system. Int Arch Allergy Immunol 112: 203–211 and the cardiovascular system.³¹Krause, D. N., Barrios, V. E., and Duckles, S. P. Melatonin receptors mediate potentiation of contractile responses to adrenergic nerve stimulation in rat caudal artery (1995) Eur. J. Pharmacol. 276, 207–213 It has also been shown to influence cell differentiation where it can either stimulate or suppress cell division depending on its concentration or the cell type.³²Hill SM, Blask DE. Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res. 1988 Nov 1;48(21):6121-6.^,33Cos, S., and Sa´nchez-Barcelo´, E. J. Modulation of the length of the cell cycle time of MCF-7 human breast cancer cells by melatonin (1995) Cancer Lett. 93, 207–212^,34Roth JA, Rabin R, Agnello K. Melatonin suppression of PC12 cell growth and death. Brain Res. 1997 Sep 12;768(1-2):63-70. In light of this, melatonin has been proclaimed to be a cure-all for everything from treating insomnia and cancer to acting as an anti-aging agent.³⁵Pierpaoli W, Dall’Ara A, Pedrinis E, Regelson W. The pineal control of aging. The effects of melatonin and pineal grafting on the survival of older mice. Ann N Y Acad Sci. 1991;621:291-313.^,36Pierpaoli, W., and Regelson, W. Pineal control of aging: Effect of melatonin and pineal grafting on aging mice (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 787–791^,37Huether G. Melatonin as an antiaging drug: between facts and fantasy. Gerontology. 1996;42(2):87-96. 

Most women with PCOS grow many small cysts on their ovaries. That is why it is called Polycystic Ovary Syndrome. Melatonin concentrations are higher in the fluid of large follicles (cysts) than in the small follicles (cysts) suggesting that increased melatonin in follicles (cysts) prior to ovulation may have an important role in ovulation processes.³⁸Nakamura Y, Tamura H, Takayama H, and Kato H (2003) Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production. Fertil Steril 80: 1012-1016.

Many women experience pain and increased symptoms during ovulation due to the spike in melatonin production. Often women call every month wondering what they did to cause a flair in their symptoms. The first question is: Where are you at in your cycle?

Increased melatonin levels are observed in women with PCOS,³⁹P Jain, M Jain, C Haldar, TB Singh, S Jain. Melatonin and its correlation with testosterone in polycystic ovarian syndrome. J Hum Reprod Sci. 2013 Oct-Dec; 6(4): 253–258.^,40Terzieva DD1, Orbetzova MM, Mitkov MD, Mateva NG. Serum melatonin in women with polycystic ovary syndrome. Folia Med (Plovdiv). 2013 Apr-Jun;55(2):10-5. patients with dysfunctional reproductive organs,⁴¹Kadva A, Djahanbakhch O, Monson J, Di WL, Silman R. Elevated nocturnal melatonin is a consequence of gonadotropin-releasing hormone deficiency in women with hypothalamic amenorrhea. J Clin Endocrinol Metab. 1998 Oct; 83(10):3653-62. in patients of HPG Axis amenorrhea, and in anorexia nervosa.⁴²Luboshitzky R, Qupti G, Ishay A, Shen-Orr Z, Futerman B, Linn S. Increased 6-sulfatoxymelatonin excretion in women with polycystic ovary syndrome. Fertil Steril. 2001 Sep; 76(3):506-10.

Melatonin Enhances the Immune Response

Short, winter-like photoperiods enhance immune function relative to those exposed to long, summer-like days. The seasonal changes in immune function is due to changes in the melatonin levels.⁴³Nelson RJ and Demas GE. Seasonal changes in immune function. Q Rev Biol 71: 511–548, 1996.^,44Champney TH, Allen GC, Zannelli M, and Beausang LA. Time-dependent effects of melatonin on immune measurements in male Syrian hamsters. J Pineal Res 25: 142–146, 1998.^,45Guerrero JM and Reiter RJ. A brief survey of pineal glandimmune system interrelationships. Endocr Res 18: 91–113, 1992.^,46Maestroni GJ. The immunoneuroendocrine role of melatonin. J Pineal Res 14: 1–10, 1993.

The physiological properties of melatonin are not limited to its neuroendocrine role in controlling circadian rhythms;⁴⁷Cassone VM: Effects of melatonin on vertebrate circadian systems. Trends Neurosci 1990, 13:457-464. several other actions have been discovered. Melatonin has been shown to increase innate and acquired immunity,⁴⁸Poon AM, Liu ZM, Pang CS, Brown GM, Pang SF: Evidence for a direct action of melatonin on the immune system. Biol Signals 1994, 3:107-17. to activate the bone marrow and lymph nodes,⁴⁹Wajs E, Kutoh E, Gupta D: Melatonin affects proopiomelanocortin gene expression in the immune organs of the rat. Eur J Endocrinol 1995, 133:754-760. to enhance NK cell activity⁵⁰Guerrero JM, Reiter RJ: A brief survey of pineal gland-immune system interrelationships. Endocr Res 1992, 18:91-113.^,51del Gobbo V, Libri V, Villani N, Calio R, Nistico G: Pinealectomy inhibits interleukin-2 production and natural killer activity in mice. Int J Immunopharmacol 1989, 11:567-573. and antibody-dependent cell cytotoxicity,⁵²Giordano M, Palermo MS: Melatonin-induced enhancement of antibody dependent cellular cytotoxicity. J Pineal Res 1991, 10:117-121. to increase T cell proliferation ⁵³Pioli C, Caroleo MC, Nistico G, Doria G: Melatonin increases antigen presentation and amplifies specific and non specific signals for T-cell proliferation. Int J Immunopharmacol 1993, 15:463-468.^,54Konakchieva R, Kyurkchiev S, Kehayov I, Taushanova P, Kanchev L: Selective effect of methoxyindoles on the lymphocyte proliferation and melatonin binding to activated human lymphoid cells. J Neuroimmunol 1995, 63:125-132. and to activate monocyte⁵⁵Morrey KM, McLachlan JA, Serkin CD, Bakouche O: Activation of human monocytes by the pineal hormone melatonin. J Immunol 1994, 153:2671-2680.^,56Lissoni P, Pittalis S, Brivio F, Tisi E, Rovelli F, Ardizzoia A, Barni S, Tancini G, Giudici G, Biondi A, Conti A, Maestroni G: In vitro modulatory effects of interleukin-3 on macrophage activation induced by interleukin-2. Cancer 1993, 71:2076-2081. and neutrophils.⁵⁷Lopez-Gonzalez MA, Calvo JR, Osuna C, Rubio A, Guerrero JM: Melatonin potentiates cyclic AMP production stimulated by vasoactive intestinal peptide in human lymphocytes. Neurosci Lett 1992, 136:150-152. Melatonin can stimulate innate immune cells, primarily leukocytes, which represents an important anti-bacterial mechanism.⁵⁸França EL, Feliciano ND, Silva KA, Ferrari CK, Honorio-França AC: Modulatory role of melatonin on superoxide release by spleen macrophages isolated from alloxan-induced diabetic rats. Bratisl Med J 2009, 110:517-522.,⁵⁹França EL, Pereira A Jr, Oliveira SL, Honorio-França AC: Chronoimmunomodulation of melatonin on bactericidal activity of human blood phagocytes. Int J Microbiol 2009, 6:1-13.

Th17 (harm) and Treg cells (protection) are both involved in the harm/protection balance of immune conditions such as autoimmunity or acute transplant rejection (miscarriage).⁶⁰Lardone PJ, Guerrero JM, Fernández-Santos JM, Rubio A, Martín-Lacave I, Carrillo-Vico A. Melatonin synthesized by T lymphocytes as a ligand of the retinoic acid-related orphan receptor. J Pineal Res. 2011 Nov;51(4):454-62.^,61Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006 Sep 22;126(6):1121-33.^,62Eberl G, Littman DR. The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer’s patches. Immunol Rev 2003;195:81–90.^,63Z Chen,  A Laurence, JJ. O’Shea. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Semin Immunol. 2007 December ; 19(6): 400–408. The differentiation of Th17 using melatonin supplementation or melatonin inducing Blue Blocker Glasses aggravates autoimmune diseases and/or can induce serious complications in pregnancy.⁶⁴Becker-André M, Wiesenberg I, Schaeren-Wiemers N, André E, Missbach M, Saurat JH, Carlberg C. Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem. 1994 Nov 18;269(46):28531-4. 

Melatonin enhances the immune response.⁶⁵Currier NL, Sun LZY, and Miller SC. Exogenous melatonin: quantitative enhancement in vivo of cells mediating non-specific immunity. J Neuroimmunol 104: 101–108, 2000.^,66Drazen DL, Klein SL, Yellon SM, and Nelson RJ. In vitro melatonin treatment enhances splenocyte proliferation in prairie voles. J Pineal Res 28: 34–40, 2000.^,67Nelson RJ and Drazen DL. Melatonin mediates seasonal adjustments in immune function. Reprod Nutr Dev 39: 383–398, 1999. A large body of evidence supports the immunoenhancing role of melatonin.⁶⁸Nelson RJ and Drazen DL. Melatonin mediates seasonal adjustments in immune function. Reprod Nutr Dev 39: 383–398, 1999. Exposure to short days (<12 h light/day) or daily melatonin supplements or melatonin increasing Blue Blocker Glasses may increase the size of the spleen.⁶⁹Vaughan MK, Hubbard GB, Champney TH, Vaughan GM, Little JC, and Reiter RJ. Splenic hypertrophy and extramedullary hematopoiesis induced in male Syrian hamsters by short photoperiod or melatonin injections and reversed by melatonin pellets or pinealectomy. Am J Anat 179: 131–136, 1987.^,70Becker J, Veit G, Handgretinger R, Atanasio A, Bruchett G, Reuner I, Niethammer D, and Das Gupta TK. Circadian variations in the immunomodulatory role of the pineal gland. Neuroendocrinol Lett 10: 65–72, 1988. Melatonin enhances both cell-mediated and humoral immune function.⁷¹Maestroni GJ. The immunoneuroendocrine role of melatonin. J Pineal Res 14: 1–10, 1993.^,72Guerrero JM and Reiter RJ. A brief survey of pineal gland immune system interrelationships. Endocr Res 18: 91–113, 1992.

Melatonin supplementation or melatonin increasing Blue Blocker Glasses of both normal and immunocompromised individuals increases antibody responses and T helper cell activity.⁷³ Maestroni GJ. The immunoneuroendocrine role of melatonin. J Pineal Res 14: 1–10, 1993.^,74Caroleo MC, Frasca AD, Nistico G, and Doria D. Melatonin as immunomodulator in immunodeficient mice. Immunopharmacology 23: 81–89, 1992.

Melatonin administration appears to stimulate humoral immunity during early B cell development in the bone marrow.⁷⁵Yu Q, Miller SC, and Osmond DG. Melatonin inhibits apoptosis during early B-cell development in mouse bone marrow. J Pineal Res 29: 86–93, 2000.^,76Maestroni GJ and Pierpaoli W. Pharmacologic control of the hormonally mediated immune response. In:  Psychoneuroimmunology, edited by Ader R. New York: Academic, 1982, p. 405–425.

Melatonin supplements and/or treatment for extended duration (e.g., Blue Blocker Glasses) induces physiological adaptations associated with winter, including reproductive regression and enhancement of certain aspects of immune function.⁷⁷Bartness TJ, Powers JB, Hastings MH, Bittman EL, and Goldman BD. The timed infusion paradigm for melatonin delivery: what has it taught us about the melatonin signal, its reception, and the photoperiodic control of seasonal responses? J Pineal Res 15: 161–190, 1993.^,78Demas GE and Nelson RJ. Short-day enhancement of immune function is independent of steroid hormones in deer mice (Peromyscus maniculatus). J Comp Physiol [B] 168: 419–426, 1998. In healthy individuals, melatonin has anti-inflammatory effects, while in those with Autoimmune conditions, melatonin is pro-inflammatory.Hardeland R. Melatonin and inflammation—Story of a double-edged blade. J. Pineal Res. 2018; 65:e12525.^79,Cho JH, Bhutani S, Kim CH, Irwin MR. Anti-inflammatory effects of melatonin: A systematic review and meta-analysis of clinical trials. Brain Behav Immun. 2021 Mar;93:245-253.^,Radogna F, Diederich M, Ghibelli L, 2010. Melatonin: a pleiotropic molecule regulating inflammation. Biochem Pharmacol 80, 1844–1852.⁸⁰

References

• 1
  Wehr TA, Duncan WC Jr, Sher L, Aeschbach D, Schwartz PJ, Turner EH, Postolache TT, Rosenthal NE. A circadian signal of change of season in patients with seasonal affective disorder. Arch Gen Psychiatry. 2001 Dec;58(12):1108-14.
• 2
  Julius Axelrod ,The Pineal Gland: A Neurochemical Transducer.Science184,1341-1348(1974).
• 3
  Wurtman RJ, Axelrod J, Phillips Ls. (1963). Melatonin synthesis in the pineal gland; control by light. science 142: 1071-1073.
• 4
  Alexandre Sasseville, Nathalie Paquet, Jean Sévigny, Marc Hébert. Blue blocker glasses impede the capacity of bright light to suppress melatonin production. J. Pineal Res. 2006; 41:73–78
• 5
  Menendez-Pelaez, A.; Howes, K.A.; Gonzalez-Brito, A.; Reiter, R.J. N-acetyltransferase activity, hydroxyindole-Omethyltransferase activity, and melatonin levels in the Harderian glands of the female Syrian hamster: changes during the light:dark cycle and the effect of 6-parachlorophenylalanine administration. Biochem. Biophys. Res. Commun., 1987, 145, 1231-1238.
• 6
  Tan, D.X.; Manchester, L.C.; Reiter, R.J.; Qi, W.B.; Zhang, M.; Weintraub, S.T.; Cabrera, J.; Sainz, R.M.; Mayo, J.C. Identification of highly elevated levels of melatonin in bone marrow: its origin and significance. Biochim. Biophys. Acta., 1999, 1472, 206-214.
• 7
  Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res. 2000 May; 28(4):193-202.
• 8
  Naranjo MC, Guerrero JM, Rubio A, Lardone PJ, Carrillo-Vico A, et. al. Melatonin biosynthesis in the thymus of humans and rats. Cell Mol Life Sci. 2007 Mar; 64(6):781-90.
• 9
  Jaworek J, Brzozowski T, Konturek SJ. Melatonin as an organoprotector in the stomach and the pancreas. J Pineal Res. 2005 Mar;38(2):73-83.
• 10
  Drazen DL, Bilu D, Bilbo SD, Nelson RJ. Melatonin enhancement of splenocyte proliferation is attenuated by luzindole, a melatonin receptor antagonist. Am J Physiol Regul Integr Comp Physiol. 2001 May;280(5):R1476-82.
• 11
  Konturek SJ, Konturek PC, Brzozowska I, et al. Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT). J Physiol Pharmacol 2007; 58:381–405.
• 12
  Constantinescu CS, Hilliard B, Ventura E, Rostami A. Luzindole, a melatonin receptor antagonist, suppresses experimental autoimmune encephalomyelitis. Pathobiology. 1997;65(4):190-4.
• 13
  Nakamura Y, Tamura H, Takayama H, Kato H. Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production. Fertil Steril. 2003 Oct;80(4):1012-6.
• 14
  Starr, J. (2011). The Effect of Melatonin on the Ovaries. The Science Journal of the Lander College of Arts and Sciences, 5(1).
• 15
  Tamura H, Nakamura Y, Korkmaz A, Manchester LC, Tan DX, Sugino N, Reiter RJ. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2009 Jul;92(1):328-43. doi: 10.1016/j.fertnstert.2008.05.016. Epub 2008 Sep 18. PMID: 18804205.
• 16
  Olcese JM. Melatonin and Female Reproduction: An Expanding Universe. Front Endocrinol (Lausanne). 2020 Mar 6;11:85. doi: 10.3389/fendo.2020.00085. PMID: 32210911; PMCID: PMC7067698.
• 17
  Voordouw B, Euser R, Verdonk R, Alberda B, deJong F, Drogendijk A, et al. Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation. J Clin Endocrinol Metab. (1992) 74:108–17.
• 18
  Tamura H, Nakamura Y, Korkmaz A, Manchester LC, Tan DX, Sugino N, Reiter RJ. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2009 Jul;92(1):328-43. doi: 10.1016/j.fertnstert.2008.05.016. Epub 2008 Sep 18. PMID: 18804205.
• 19
  Cruz, M.H.; Leal, C.L.; Cruz, J.F.; Tan, D.X.; Reiter, R.J. Essential actions of melatonin in protecting the ovary from oxidative damage. Theriogenology 2014, 82, 925–932.
• 20
  Wurtman, R.J.; Axelrod, J.; Potter, L.T. The uptake of H3-melatonin in endocrine and nervous tissues and the effects of constant light exposure. J. Pharmacol. Exp. Ther. 1964, 143, 314–318.
• 21
  Nakamura, Y.; Tamura, H.; Takayama, H.; Kato, H. Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production. Fertil. Steril. 2003, 80, 1012–1016.
• 22
  Tamura H, Jozaki M, Tanabe M, Shirafuta Y, Mihara Y, Shinagawa M, Tamura I, Maekawa R, Sato S, Taketani T, Takasaki A, Reiter RJ, Sugino N. Importance of Melatonin in Assisted Reproductive Technology and Ovarian Aging. Int J Mol Sci. 2020 Feb 8;21(3):1135.
• 23
  Cassone V.M., Chesworth M.J., Armstrong S.M. Entrainment of rat circadian rhythms by daily injection of melatonin depends upon the hypothalamic suprachiasmatic nuclei. Physiol. Behav. 1986;36:1111–1121.
• 24
  McMillen I.C., Houghton D.C., Young I.R. Melatonin and the development of circadian and seasonal rhythmicity. J. Reprod. Fertil. Suppl. 1995;49:137–146.
• 25
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