Pathophysiology Review
Located at the roof of the posterior portion of the third ventricle of the brain, the pineal gland is an endocrine organ with diverse roles. It has access to a rich supply of blood, and its hormonal products affect virtually every organ system in the body. The principle cellular components of the pineal gland are pinealocytes, which are arranged into cords or follicles separated by connective tissue septa.
The pineal gland is innervated by the sympathetic nervous system, via the superior cervical ganglion. This innervation is essential for the rhythmic metabolism of indolamines, such as tryptophan and serotonin and their derivatives, as well as the pineal gland’s endocrine functions. Besides sympathetic innervation, the pineal gland also receives axons from the brain, entering through the stalk. There is strong evidence to suggest parasympathetic, commissural, and peptidergic innervation as well.
Melatonin Synthesis
Melatonin is the primary substance secreted by the pineal gland, which modulates the adrenal (HPA) axis during clinical illness, the serotonergic system in psychiatric disease, and the body’s general response to stress.
Melatonin is the major neuroendocrine modulator of annual and circadian biorhythms in the body, and has a far-reaching biological influence over most of the autonomic, hormonal, and behavioral functions of the human organism. With its unique ability to pass through all blood barriers in the body, melatonin acts as the central hub of physiological function, orchestrating the complex internal processes of the body in conjunction with various external stimuli. This role has resulted in melatonin being coined the “connecting chemical” — a potent hormone that conjoins the mind, the body, and the environment.
The pineal gland is innervated by the sympathetic nervous system, via the superior cervical ganglion. This innervation is essential for the rhythmic metabolism of indoleamines, such as tryptophan and serotonin and their derivatives, as well as the pineal gland’s endocrine functions. Besides sympathetic innervation, the pineal gland also receives axons from the brain entering through the stalk. There is strong evidence to suggest parasympathetic, commissural, and peptidergic innervation as well.1
Melatonin is synthesized within the pineal gland from tryptophan.2 The secretion pattern is generated within the suprachiasmatic nucleus (SCN). Synthesis occurs upon exposure to darkness, with the increased activity of serotonin-N-acetyltransferase. By the action of hydroxyindole-O-methyltransferase (HIOMT), N-acetylserotonin is converted to melatonin. Melatonin is then rapidly secreted into the vascular system and, possibly, into the cerebrospinal fluid.3
Peripheral tissues, such as the retina and the gut, are also known to synthesize melatonin.4
Melatonin production in humans begins at the age of approximately 3 months. Peak nocturnal levels occur between the ages of 1-3 years. Secretion levels decline as the individual develops sexual maturity, and drop 80% by the time adulthood is reached, diminishing even further with age.5
Melatonin secretion levels are low during the day and high at night, peaking at about 2:00-3:00 a.m. for most healthy individuals. This circadian rhythm makes melatonin one of the best markers for circadian rhythm disruption available at this time.
Diurnal and Circadian Rhythms
(Repinted, with adaptations, by permission of Great Smokies Laboratory)
Melatonin’s diurnal rhythm is synchronized by the light-dark cycle, and is strongly affected by day length, artificial illumination, electromagnetic energy, exercise, and other social and environmental influences. Melatonin rhythms also reflect the biological process of aging, with secretion levels peaking in childhood and gradually diminishing over an individual’s life span. Operating much like an internal aging clock, melatonin exerts regenerative and integrative influences that may explain the age-dependent decrease in immune function that can lead to malignancy, senescence, and eventually death.
Light-Dark Cycles
Melatonin is synthesized and secreted during the dark phase of the day. The secretion rhythm is endogenous (internally generated), and generally persists in the absence of time cues, assuming a period that deviates only slightly from 24 hours. Thus, it is a true circadian rhythm.6,7
Melatonin secretion is related to the length of the night. The longer the night, the longer the duration of the secretion. If humans are kept strictly in darkness for 14 hours per day over a period of one month, the duration of melatonin secretion expands to cover almost the entire dark period. Conversely, if a subject is exposed to light for 14 hours per day, the duration of secretion shrinks to 10 hours, accompanied by concomitant changes in body temperature and sleep.8
Light Exposure
Light exposure of the retina alters the amount of serotonin metabolized to melatonin, via the neural pathways that connect the retina to the pineal gland.9 The individual’s visual system must be intact for proper synchronization of the melatonin rhythm. Blind persons commonly exhibit a pronounced lack of circadian rhythm, with free-running cycles generated internally despite the presence of other external time cues in their environment.10,11
Exposure to sufficient levels of light at night can rapidly reduce melatonin production.12 One investigator found that after human subjects were exposed to one hour of light at midnight using 3000, 1000, 500, 350, and 200 lux intensities, melatonin levels dropped by 71, 67, 44, 38, and 16%, respectively.13
The spectrum of light that most dramatically inhibits melatonin secretion is green band light (540nm), which corresponds to the rhodopsin absorption spectrum in humans.14 This observation is of considerable importance, not only to understand the physiological effects of melatonin, but to effectively regulate circadian rhythms- a crucial component in the treatment of Seasonal Affective Disorder (SAD) and other health problems.15
Electromagnetic Energy
Laboratory studies with rats have consistently shown that exposure to electromagnetic fields can disrupt pineal function and circadian secretion patterns of melatonin.16-19 One study on humans who used electric blankets concluded that periodic exposure to even low frequency electric or magnetic fields can significantly affect pineal gland function.20 In an interesting study on electric power, pineal function, and breast cancer, investigators postulated that higher rates of breast cancer in industrialized nations may be due to increased light-at-night (LAN) and electromagnetic fields (EMF) suppressing human melatonin production.21 Many modern occupations and conditions-including living near a power line-can drastically increase EMF exposure.22,23
Seasonal Variations
Seasonal changes can affect melatonin secretion patterns by advancing or delaying secretion phase shifts.24,25 The exact nature of these variations is still not clearly understood, although factors such as length of photoperiod, temperature, and effect of seasonal changes on individuals may all be contributing factors.26
Effect of Drugs
Antidepressants and other psychotropic drugs affect the synthesis and release of melatonin. Some monoamine oxidase-inhibiting drugs such as clorgyline and tranylcypromine seem to enhance plasma melatonin levels, while others, such as deprenyl, register no significant change.27-30
Tricyclic antidepressants that influence monoamine uptake and beta-adrenoceptors trigger a decrease in plasma melatonin in rodent experiments; however, human patients treated with the tricyclic desipramine show either no change, or a notable rise, in nighttime melatonin levels.27,30 Although tricyclics and fluvoxamine are both associated with increases in melatonin secretion in humans, fluoxetine (commonly known as Prozac) reportedly lowers blood melatonin levels.31
One group of researchers conjectured that sleep disruption associated with some nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, and acetaminophen may be a result of decreased prostaglandin production, which can suppress melatonin secretion.32 Both ibuprofen and indomethacin significantly reduce melatonin plasma levels and delay the nocturnal rise of the circadian rhythm.33,34
ß-blockers can also significantly alter melatonin levels. Hypertensive patients undergoing chronic beta-adrenoreceptor blocker treatment with propranolol and ridazolol showed considerably diminished melatonin secretion.35 Propranolol hydrochloride also induced a noticeable decrease in serum melatonin levels in schizophrenic patients.36
Exercise
Research suggests that daytime exercise can increase melatonin levels. While some studies report that the increase occurs during or immediately after physical activity,37-39 others point to a delayed rise that takes place in the second half of the dark phase.40 One group of researchers found that nighttime exercise effectively blunts the nocturnal melatonin surge.41 And, in a unique study undertaken by Swiss researchers, daily 1-hour morning walks outdoors were shown to phase advance the onset and/or offset of melatonin secretion, and were twice as effective as low dose artificial light therapy in relieving the symptoms of SAD.42
