The Pineal Gland and Melatonin

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Chapter 15

The Pineal Gland and Melatonin

The human pineal gland is the most poorly understood endocrine organ. Although it has been described as a dispensable gland in humans, the pineal gland converts light information into a hormonal signal in the form of melatonin. Melatonin is a chronobiotic hormone with multiple pleomorphic actions. The hormone transmits information regarding day length which helps organize circadian and seasonal rhythms. The mammalian pineal gland plays numerous modulatory roles in the regulation of sleep, body temperature, reproductive, and immune function. However, there is still little evidence that the pineal gland has a vital regulatory role in human biology. For example, there is no clearly documented severe morbid phenotype produced following pinealectomy. Despite the lack of evidence that the pineal gland is essential in human biology, there is growing evidence that exogenously administered melatonin may have therapeutic value in treating several disorders. Moreover, there are a variety of tumors of the pineal gland region that can impose substantial morbidity and mortality for the patient if not quickly diagnosed and appropriately treated.

Pineal Gland

The human pineal gland weighs approximately 100 to 200 mg and is roughly 5 to 9 mm in length, 1 to 5 mm in width, and 3 to 5 mm in thickness. The name pineal is derived from the pinecone-like structure of the gland. The pineal gland is formed by a central core of lobules surrounded by a cortex with a diffuse distribution of neurons. The gland is an embryologic outgrowth of the roof of the third ventricle and at birth is attached to the posterior roof of the third ventricle between the posterior commissure and the dorsal habenula, located on top of and between the superior colliculi.

Histologically, the pineal gland is composed of pinealocytes, which have endocrine cell properties that include cytoplasmic processes terminating on fenestrated capillaries. Neuroglia are found unevenly distributed surrounding the pinealocytes. The pineal gland belongs to circumventricular organs of the CNS that surround the third ventricle and thus are not protected by the blood-brain barrier.

Calcareous deposits are a common radiographic characteristic of the gland. This material is composed of calcium and magnesium salts, hydroxyapatite, and trace elements. These deposits can be present at birth but increase in density with age. The impact of these deposits on pineal gland function is uncertain.

Neural Innervation of The Pineal Gland

Phylogenetically, the pineal gland is derived from photoreceptor cells; however, these properties have been lost in humans. The mammalian pineal gland does not have photoreceptor activity but rather receives photosensory information from the neuroretina. This information is relayed through the retinohypothalamic tract to the suprachiasmatic nucleus (SCN) of the hypothalamus, which functions as a circadian oscillator or clock (Fig. 15-1). Fibers from the SCN then descend to the spinal cord, projecting to the superior cervical ganglia, from which postganglionic adrenergic neurons return to innervate the pineal gland. These fibers contain norepinephrine and neuropeptide Y. Through this pathway, melatonin synthesis is controlled and its rhythm entrained (synchronized) to the 24-hour light/dark cycle (see below). It is generated in the SCN by a closed loop of negative feedback of clock gene expression.1

The pineal gland also receives parasympathetic and peptidergic innervation originating in the hypothalamus, mesolimbic system, and visual structures. These fibers contain a number of neurotransmitters such as somatostatin, serotonin, and histamine. The pineal gland also contains gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), vasotocin, and other peptides whose roles are yet to be defined.

Melatonin

The word melatonin is a derivative of the Greek words melas and tonein, coined because of the property of melatonin to lighten amphibian skin.2 Melatonin is N-acetyl-5-methoxytryptamine, an indolamine derivative of tryptophan. The molecule is extremely well conserved across the phyla and has been identified in all major taxa, including bacteria, unicellular eukaryotes, many plants species, and all animals.3 In the vertebrate, melatonin is primarily secreted by the pineal gland, although a variety of other tissues, including the retina, bone marrow, skin, lymphocytes, and gastrointestinal tract, also synthesize the hormone. Melatonin derived from the gastrointestinal tract can be released into the circulation after ingestion of high dietary tryptophan.4

Synthesis and Secretion of Melatonin

Through the neuroretinal pathways described above, the pineal gland becomes a neuroendocrine transducer, transmitting the SCN message into a hormonal code which signals that light or darkness has arrived. Indeed, the main function of the pineal gland is to translate SCN activity into the rhythmic release of melatonin, which in turn helps synchronize several daily and seasonal cycles. The synthesis of melatonin is presented in Fig. 15-2. The hormone is synthesized from the amino acid tryptophan, which is converted into serotonin prior to being processed into melatonin. Melatonin synthesis and secretion are greater during the dark phase compared to the light phase of the cycle. During the light phase of the photoperiod, SCN activity is high, resulting in low norepinephrine levels. Under reduced adrenergic activity, tryptophan is converted into serotonin in a two-step process via the intermediary, 5-hydroxytryptophan. At this point, serotonin does not come into contact with the enzyme responsible for converting it into melatonin. Therefore, plasma levels of melatonin are low during the light phase. However, with the arrival of the dark period, SCN activity becomes quiescent, and noradrenergic activity increases, resulting in activation of β-adrenergic receptors (and to a lesser extent α-adrenergic receptors) on the pinealocyte. The β-adrenergic receptors are coupled to cyclic adenosine monophosphate (cAMP)/protein kinase A signaling pathways that stimulate melatonin synthesis (Fig. 15-3). Stimulation of α-adrenergic receptors potentiates β-adrenergic function, resulting in a cascade that mobilizes calcium ions, phosphatidylinositol, diacylglycerol, and protein kinase C.5 This process requires serotonin to be first converted into N-acetyl serotonin by the enzyme serotonin-N-acetyltransferase, which in turn is converted into melatonin after coming into contact with the enzyme hydroxyindole-O-methyltransferase (HIOMT).6 The longer the dark phase, the longer the duration of melatonin secretion.

Melatonin is not stored after synthesis but merely diffuses out of the pineal gland into the blood stream and cerebrospinal fluid. In the transition from light to dark, plasma melatonin concentrations increase from 2 to 10 pg/mL to 100 to 200 pg/mL.7 Melatonin levels start to rise during the evening, reach maximum levels in the middle of the night, and start decreasing in the early morning before sunrise. Although the melatonin rhythm is highly responsive to the light cycle, it does persist when people are placed for a few days in a dark room and does not immediately phase shift when the light schedule is altered.7 This indicates that the rhythm is not simply generated by the light/dark cycle but is free running and modulated by endogenous signals probably arising in the SCN. Indeed, the rhythm is abolished by lesioning of the SCN and persists, albeit in modified form, in the blind.8 The day-to-day pattern of melatonin secretion is extremely stable within an individual.9 However, the melatonin rhythm varies widely among individuals, in part owing to genetic determinants.9a In fact, a small number of healthy persons have no detectable melatonin in plasma at any time of day.10

Melatonin has a bi-exponential half-life, with a first distribution T½ of 2 minutes and a second of 20 minutes. The hormone is lipophilic and enters tissues rapidly. Up to 70% of melatonin is bound to albumin in plasma.11 In addition to blood, saliva, and urine, melatonin is also found in cerebrospinal fluid (CSF), the anterior chamber of the eye, and in many reproductive fluids, including semen, amniotic fluid, and breast milk.12 Melatonin levels in plasma, CSF, saliva, and urine become undetectable following removal of the pineal gland, demonstrating that the pineal gland is the main source of melatonin in these compartments.13

Melatonin secretion varies across the life cycle. Secretion of the hormone begins in the fourth month of postnatal life and then increases rapidly, peaking between the ages of 1 and 3. Nocturnal melatonin secretion then starts a marked decline over each decade of life14 (Fig. 15-4). Nocturnal melatonin concentrations can also be affected by drugs that interfere with the transmission of neurotransmitter signals to the pineal gland. These drugs include β-blockers, caffeine, and ethanol.1517 Nocturnal melatonin secretion is also suppressed by exposure to environmental lighting. Indeed, there is a dose-dependent and spectral-sensitive acute suppressive effect of light on melatonin.18,19 Even low light levels found indoors can suppress nocturnal melatonin production. In addition to light, exercise and postural changes decrease plasma melatonin levels.20,21

Melatonin Receptors

In the mammal, there are at least two melatonin receptors, designated MT1 and MT2, which belong to the superfamily of G protein–coupled receptors containing the usual seven transmembrane domains. A third melatonin binding site, MT3, was found to be the enzyme quinone reductase 2.22 These receptors have distinct structures, chromosomal localization, and pharmacologic properties.23 The MT1 and MT2 receptors are differentially expressed across the nervous system. The highest density is found in the SCN, followed by the anterior pituitary and the retina.24 Studies have shown that the MT1 receptor in the SCN allows melatonin to inhibit firing of SCN neurons during the nighttime.24 The SCN MT2 receptor possibly mediates the effect of melatonin on SCN circadian rhythms.24 Both receptors are co-localized within the SCN and are coupled to multiple signaling pathways, with suppression of cyclic AMP production through a Gi-dependent process being the most common.23 The receptors can also stimulate phospholipase C, affecting various ion channels, as well as stimulating the mitogen-activated protein kinase cascade and the estrogen-dependent signaling cascade.25 Melatonin is a small, lipophilic compound which easily crosses membranes. In this regard, melatonin has been shown to bind to specific nuclear receptors of the retinoic acid receptor family26,27 and to calmodulin. Melatonin receptors have also been identified in the heart, kidney, liver, and many other peripheral tissues.28,29

The MT1 and MT2 receptors have different profiles for receptor desensitization. Exposure of the MT1 receptor to supraphysiologic concentrations of melatonin causes an increase in MT1 receptor density, with a concurrent decrease in affinity and functional sensitivity.24 In contrast, exposure of the MT2 receptor to physiologic concentrations of melatonin can induce a concentration and time-dependent receptor desensitization and internalization.30 The interplay between desensitization of the MT1 and MT2 receptors to daytime and nighttime physiologic concentrations of melatonin may promote changes in melatonin receptor function throughout the human circadian cycle. With the SCN ultimately controlling the production of melatonin, a feedback loop is created that may use melatonin as the regulatory control of SCN firing and phase-shifting functions.31 Desensitization of MT1 and MT2 receptors needs to be taken into account when administering melatonin to patients.

Actions of Endogenous and Exogenous Melatonin

Seasonal and circadian rhythms serve an essential function in all living organisms. In conjunction with the SCN, melatonin signals the time of day and time of year to cells throughout the body and in so doing, modulates seasonal and circadian rhythms.

Seasonal variations in day length have reciprocal effects on melatonin secretion and can thus differentially affect plasma melatonin levels, depending on the location of the human population. For example, individuals living at high northern latitudes have a lengthening of melatonin secretion during winter nights.33 This may help explain how changes in the seasons affect reproductive vitality. In the laboratory setting, artificial shorting or lengthening of “night” will also adjust the duration of melatonin secretion.34

Circadian rhythms are biological processes that have a 24-hour periodicity even in the absence of external cues. Melatonin is involved in regulating several circadian cycles, including core body temperature and the sleep/wake cycle. The temporal organization of human circadian rhythms has been assigned the following terms: “biological day,” “biological night,” “biological dawn,” and “biological dusk.”35 During this 24-hour cycle, rising melatonin levels are associated with decreasing core body temperature, cortisol levels, and alertness. As melatonin levels wane, core body temperature, REM sleep propensity, and cortisol levels increase. It remains unclear whether there is a causal relationship between melatonin and these changes in the sleep/wake cycle. However, exogenously administered melatonin can phase shift body temperature, sleep timing, and the endogenous melatonin cycle.32 The ability of melatonin to phase shift circadian cycles has been exploited in the treatment of jet lag and shift-work disorders (see below).

Sleep

The evening rise in melatonin precedes bedtime by about 2 hours and suggests a causal relationship. Indeed, the peak in plasma melatonin occurs when alertness is at its nadir. However, the sleep/wake cycle is regulated by both homeostatic and circadian processes and is only partially influenced by melatonin. The Smith-Magenis syndrome illustrates the association between melatonin and the sleep/wake cycle. The manifestations of this disorder include excessive daytime sleepiness and insomnia at night. Treatment of these patients with a β-adrenergic blocker decreases daytime melatonin levels and diminishes daytime sleepiness.36 Administration of physiologic and pharmacologic doses of melatonin to normal sleepers induces soporific symptoms. However, evidence of a direct relationship between endogenous melatonin and insomnia has been mixed.37,38 The number of reports that have measured plasma melatonin concentrations in sleep disorders is surprisingly low, considering its use as sleep-promoting agent for insomnia. Sleep disturbances have been described in some but not all pinealectomized patients, and administration of melatonin has sometimes been found to be efficacious in this setting.39

Although the exact role of endogenous melatonin in regulating human sleep remains to be fully elucidated, exogenous melatonin administration (0.1 to 0.3 mg) resulting in physiologic levels of melatonin will promote the onset and maintenance of sleep.32 Both a 1997 and a 2005 meta-analysis showed that melatonin administration decreases sleep latency, increases sleep efficiency, and increases total sleep duration in patients with primary insomnia.40,41 However, a meta-analysis published in 2006 which included patients with secondary causes of insomnia produced less clear-cut results.42

The sleep-promoting effect of melatonin has been linked to the inhibition of neuronal activity through activation of SCN MT1 receptors.43 A synthetic melatonin agonist, Ramelteon, which selectively activates MT1 and MT2 melatonin receptors, has been approved for the treatment of insomnia. Ramelteon shows 10-fold higher binding affinity for the MT1 compared to the MT2 receptor and 17 times higher affinity than melatonin for either receptor. The drug shows no affinity for a large number of other G protein–coupled receptors, enzymes, and neurotransmitter channels. In addition to Ramelteon, there are several other melatonin agonists under development.24

Jet Lag

Jet lag is a syndrome associated with transmeridian travel resulting in disturbances to circadian rhythms. Manifestations of jet lag include problems sleeping, malaise, fatigue, and reduced performance. A similar syndrome may result from shift work and rarely from the transition to daylight savings time. Eastbound travel is generally associated with worse symptoms than westbound travel. The severity of jet lag is also proportional to the number of time zones crossed. Left untreated, the relationship between endogenous rhythms and environmental cues will come back into synchrony over several days to a week. The ability of melatonin to speed up the process of resynchronization accounts for its efficacy in the treatment of jet lag. Phase shifting of the neuronal firing rhythms has been linked to activation of the MT2 receptor at dusk, although MT1 may also be involved.44

For air travelers crossing five or more time zones going in the eastward direction, melatonin has been found to be effective in treating jet lag when administered close to the target bedtime at the travel destination.45 Doses from 0.5 to 5 mg are found to be effective. Treatment should begin the first evening upon arrival to the destination. Side effects of melatonin in this setting include daytime sleepiness, especially with the higher doses, dizziness, headaches, and loss of appetite.45 In addition to melatonin administration, proper nutrition, going to sleep according to the new time zone, exercising, and maximizing light exposure when awake can help alleviate jet lag symptoms.

Similar to individuals with jet lag, shift workers often have symptoms of fatigue, sleep disturbances, and gastrointestinal problems.46 Studies have observed marked variability in circadian melatonin profile in these workers.47 When administered at the desired bedtime during a night shift, melatonin seems to improve sleep and increase daytime alertness.46

Disorders in the sleep/wake cycle, core body temperature, and cortisol secretion are very common in blind people with no significant light perception.48 Many blind individuals have abnormal melatonin or 6-sulfatoxymelatonin circadian profiles.49,50 In these settings, melatonin has proven effective in phase-shifting the circadian clock and in so doing, stabilizing sleep onset and sometimes improving quality and duration of sleep.49,51

Reproduction

In seasonal-breeding mammals, melatonin is involved in regulating the breeding cycle.52 The effects of melatonin on the reproductive system are generally antigonadotropic. Melatonin inhibits secretion of the gonadotropin hormones LH and FSH. This inhibitory affect is most likely due to inhibition of GnRH from the hypothalamus.53 For seasonal-breeding animals, seasonal changes in day length and thus melatonin secretion will up-regulate or down-regulate the gonadal axis. For example, during the shorter period of daylight that accompanies the nonbreeding season, melatonin levels are increased and down-regulate the gonadal axis. As the breeding season approaches and length of daylight increases, melatonin levels fall, allowing rejuvenation of the gonads.

Humans are not seasonal breeders, but melatonin may mediate the moderate seasonal fluctuations observed in human reproductive function.3 The increased conception rate seen in northern latitudes during the summer season has been reported to be caused by changes in gonadotropin induced by changes in melatonin secretion. Melatonin levels have been reported elevated in male infertility54 and in men with hypogonadotropic hypogonadism.55,56 Moreover, elevated melatonin levels have been reported in women with stress- and exercise-induced amenorrhea and in men with infertility.57 Exogenous melatonin administration has been shown to suppress LH levels in men and women and to reduce sperm motility in men.58

Melatonin has also been implicated in sexual maturation, where it may have inhibitory action on the onset of puberty. It has been proposed that a decline of melatonin below a threshold value may be a signal that activates GnRH pulsation in early puberty.3 Circumstantial evidence that melatonin is involved in sexual maturation includes the observation that children with precocious puberty have lower plasma melatonin levels, whereas children with delayed puberty exhibit higher nocturnal melatonin concentrations. However, a causal relationship between the pineal gland and human reproductive function is far from clear.

Temperature

Body temperature and plasma melatonin levels have a reciprocal profile; the 24-hour temperature nadir correlates with peak plasma melatonin levels.59 It has been estimated that approximately half of the nighttime decline in core temperature is induced by melatonin.60 Supporting a causal relationship between melatonin and body temperature are studies showing that exogenously administered melatonin will decrease body temperature in humans.61

Immune System and Cancer

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