CHAPTER 10 PINEAL GLAND

CHAPTER 10 PINEAL GLAND
Principles and Practice of Endocrinology and Metabolism

CHAPTER 10 PINEAL GLAND

RUSSEL J. REITER

Morphology and Innervation

Gross Anatomy

Innervation

Histology
Indoleamine Metabolism

Melatonin

Serotonin
Influence of Hormones and Drugs on Melatonin Secretion
Plasma Levels of Melatonin and Its Metabolism
Factors Influencing Plasma Melatonin Rhythm

Light–Dark Cycle
Age and Sexual Maturation

Aversive Stimuli

Possible Sex Steroid Feedback
Clinical Implications

Sexual Maturation

Ovulatory Relationships

Psychological Interrelationships

Sleep

Jet Lag and other Biologic Rhythm Disorders

Tumor Growth

Free Radical Scavenging
Conclusion
Chapter References

MORPHOLOGY AND INNERVATION
GROSS ANATOMY
The pineal gland, so called because of its resemblance to a pine cone (Latin pineas), is a multifaceted endocrine organ whose secretory products directly or indirectly affect every organ and cell in the body. Embryologically, it is derived from neuroectoderm as an outgrowth of the diencephalon. In adults, it is attached to the posterodorsal aspect of the diencephalon, and its proximal portion is invaginated by the pineal recess of the third ventricle (Fig. 10-1). The gland weighs ~130 mg, with great individual variation seen, and is ~1 cm long. The blood supply to the gland is derived from the posterior choroidal branches of the posterior cerebral arteries. The pineal gland has a copious blood supply. In advanced age, it may acquire calcium deposits (corpora arenacea, acervuli), which are visible on skull radiographs.

FIGURE 10-1. Midsagittal view of the human brain showing the relationship of the pineal gland to other neural structures.

INNERVATION
The pineal gland is innervated by sympathetic axons and by axons coming directly from the brain.1 Postganglionic sympathetic axons arrive in the pineal from perikarya located in the superior cervical ganglia. The cell bodies of the preganglionic fibers that end in the ganglia are located in the intermediolateral cell column of the upper thoracic cord. The neurons in the intermediolateral cell columns receive terminals from, among other sources, perikarya in the hypothalamus, possibly in the paraventricular nuclei; these nuclei are connected to the supra-chiasmatic nuclei, which receive a prominent input from the ganglion cells of the retinas through the retinohypothalamic tract. Through this complex series of neurons, the retinas are functionally related to the pineal gland. Sympathetic innervation of the pineal is essential for the rhythmic metabolism of indoleamines and for the pineal’s endocrine functions. The sympathetic neurotransmitter mediating the cyclic production of pineal indoleamines is norepinephrine.
Besides sympathetic innervation, the pineal gland receives axons directly from the brain that enter through the stalk. The function of these fibers relative to the physiology of the pineal is unknown.
HISTOLOGY
The major cellular elements within the pineal gland are the pinealocytes, which are arranged into cords or follicles separated by connective tissue septa. With advancing age, the septa become more prominent. Ultrastructurally, the pinealocytes have one to several cytoplasmic processes that typically terminate near the many capillaries perfusing the gland. The nerve endings in the pineal gland usually lie close to the pinealocyte processes in the perivascular spaces, but true morphologic synapses are not obvious.
INDOLEAMINE METABOLISM
MELATONIN
Within the pinealocyte, tryptophan, an amino acid taken up from the blood, is metabolized to a variety of potential hormones (Fig. 10-2).2 The compound that has been most thoroughly investigated is N-acetyl-5-methoxytryptamine, or melatonin. Tryptophan is initially metabolized to serotonin (5-hydroxytryptamine); the concentration of this monoamine in the pineal gland exceeds that in any other organ. Especially during the daily dark period, serotonin is N-acetylated by the enzyme serotonin N-acetyltransferase to form N-acetylserotonin.3 The activity of N-acetyltransferase increases many-fold during darkness (Fig. 10-3). N-acetylserotonin is converted to melatonin by the action of hydroxyindole-O-methyltransferase. Once formed, melatonin is rapidly secreted into the blood vascular system and, as a consequence, plasma melatonin levels typically are highest at night, when pineal melatonin production is greatest.

FIGURE 10-2. Interactions of postganglionic sympathetic neurons with the endocrine unit of the pineal gland, the pinealocyte, and the conversion of tryptophan to a variety of indole products. Within the pinealocyte, cyclic adenosine monophosphate (AMP) acts as a second messenger to stimulate the activity of serotonin N-acetyltransferase (NAT), primarily during darkness. Serotonin also is acted on by hydroxyindole-O-methyl-transferase (HIOMT) to form 5-methoxytryptamine, and by monoamine oxidase to form 5-hydroxyindole-3-acetylaldehyde. Melatonin is a major secretory product of the pineal gland. (Modified from Reiter RJ, MacLeod RM, Müller EE, eds. Neuroendocrine perspectives, vol 3. New York: Elsevier, 1984:350.)

FIGURE 10-3. Pineal, blood, and urinary rhythms of various constituents. Methods are available for estimating blood and urinary levels of melatonin and its metabolites. The shaded area in the right half of the figure represents the daily dark period. (Ac Co A, Acetyl coenzyme A; CoA, coenzyme A; S Ad M, S-adenosyl methionine; S Ad H, S-adenosyl homocysteine; CNS, central nervous system.) (From Reiter RJ. Pineal indoles: production, secretion and actions. In: Muller CE, MacLeod RM, eds. Neuroendocrine perspectives, vol 13. Amsterdam: Elsevier, 1984:358.).

SEROTONIN
Hydroxyindole-O-methyltransferase also acts directly on serotonin, converting it to 5-methoxytryptamine (see Fig. 10-2), a compound that has been proposed as a pineal hormone. Serotonin also is metabolized by monoamine oxidase; the product is eventually converted to 5-methoxytryptophol and 5-methoxyindoleacetic acid, the former of which possibly is released from the pineal.
INFLUENCE OF HORMONES AND DRUGS ON MELATONIN SECRETION
Most of what is known about the interactions of the postganglionic neurotransmitter norepinephrine with the pinealocyte comes from observations in animals, although the relationships probably are similar in humans. Norepinephrine is released into the synaptic cleft, primarily during the daily dark period, after which it acts primarily on b-adrenergic receptors on the pinealocyte membrane, where it stimulates cyclic adenosine monophosphate production and, eventually, N-acetyltrans-ferase activity and melatonin synthesis (see Fig. 10-2).4 Alpha receptors on the pinealocyte membrane also may be involved in mediating the nocturnal rise in melatonin. In humans, the peripheral infusion of isoproterenol, a b-receptor agonist, does not increase blood levels of melatonin as readily as it does in some animals. In addition, orciprenaline and L-dopa are ineffective in altering circulating melatonin in humans. The inability of isoproterenol to stimulate human pineal melatonin production may relate to the relative insensitivity of the pinealocyte b-receptors to the agonist throughout most of the day; animal studies have shown that either the number of receptors or their affinity for the ligand is greatly increased at night.5 Circulating norepinephrine may be relatively ineffective in promoting pineal melatonin production because the sympathetic nerve endings in the pineal gland have an active uptake mechanism for the catecholamine, thereby protecting the pinealocytes from circulating norepinephrine.
Other drugs that seem incapable of altering blood melatonin levels in humans include scopolamine, amphetamine, thyrotropin-releasing hormone, luteinizing hormone–releasing hormone, and desaminocys-D-arg-vasopressin.5 Both clonidine and dexamethasone have been reported to lower plasma levels of melatonin. In general, pineal melatonin production seems to be out of the usual endocrine feedback loop.
PLASMA LEVELS OF MELATONIN AND ITS METABOLISM
Plasma levels of melatonin seem to reflect closely the amount being synthesized and secreted by the pineal gland (see Fig. 10-3).6 When pineal melatonin production increases at night, plasma levels rise accordingly. In the few individuals in whom the pineal has been surgically removed because of tumors in the epithalamic region, plasma levels of melatonin either are severely depressed or are undetectable.7 In animals, pinealectomy is associated with very low or nonmeasurable amounts of melatonin in plasma.
The nocturnal rise in plasma melatonin levels has been measured by bioassay, radioimmunoassay, and gas chromatography–mass spectrometry.7a Depending on the technique used, daytime levels of plasma melatonin range from undetectable to 20 pg/mL. At night, values may increase to 300 pg/mL; however, with the most specific methods, nighttime levels typically are <50 pg/mL. Short-term rises may be superimposed on the 24-hour cycle of melatonin production because of the episodic secretion of melatonin by the pineal gland. Although the amplitude of the circadian melatonin varies widely between individuals, the rhythm is highly reproducible within each person.
Most melatonin in the plasma may be bound to proteins, especially albumin. Melatonin readily penetrates cell membranes and tissue barriers (e.g., the blood–brain barrier). Some of its primary sites of action are undoubtedly in the central nervous system (see ref. 7b). Because of its rapid metabolism, usually <1% of exogenously administered melatonin escapes into the urine in unmetabolized form.
Melatonin is enzymatically degraded in at least two sites, the liver and the brain (see Fig. 10-3).2 In animals, melatonin is rapidly metabolized in the liver. Humans with hepatic cirrhosis reportedly have higher than normal daytime levels of plasma melatonin, which implicates the liver as the primary site of its metabolism. In addition, the half-life of plasma melatonin is longer in humans with impaired liver function than in those with normal liver function.
In the liver, melatonin is chiefly metabolized to 6-hydroxymelatonin; this is conjugated to sulfuric acid and, to a much lesser extent, to glucuronic acid. A small amount of melatonin is converted to N-acetylserotonin in the liver and appears in the blood as a sulfate or glucuronide conjugate. Melatonin taken up by the central nervous system is converted in part to N-acetyl-5-methoxykynurenamine, which, along with the hepatic metabolites of melatonin, is excreted in the urine.
Besides its enzymatic degradation, melatonin is nonenzymatically metabolized when it scavenges free radicals. Melatonin’s ability to scavenge the highly toxic hydroxyl radical is one of the newly discovered functions of this widely acting hormone.
FACTORS INFLUENCING PLASMA MELATONIN RHYTHM
LIGHT–DARK CYCLE
The primary factor determining plasma melatonin levels is the prevailing light–dark environment.8 The rhythmic production and secretion of melatonin is synchronized by the light–dark cycle. Typically, daytime is associated with low plasma melatonin levels and nighttime is associated with high levels (see Fig. 10-3).6 Blind humans with no retinal light perception exhibit free-running melatonin cycles, with periods of ~24.7 hours. In these persons, the highest plasma melatonin values can occur either at night or during the day.9
The rise in plasma melatonin levels in sighted humans may actually precede the removal of artificial light at bedtime.5 Short-term dark exposure during the day typically is not associated with increased circulating melatonin levels. When persons are exposed to light during the normal dark period, however, plasma melatonin levels drop rapidly if the light has a brightness of 2500 lux or more (2500 lux is roughly four to five times the intensity of normal room light but considerably less than the intensity of sunlight).10 Individuals awakened at night and exposed to darkness or low light intensities (<300 lux) typically do not exhibit a marked alteration in the rhythmic production of melatonin.
When the light–dark cycle is shifted, such as in transmeridian travel or with a new rest–activity schedule, the melatonin rhythm also is shifted; however, the change is not immediate.11 Thus, if humans are phase-shifted by 12 hours, elevated levels of blood melatonin and its urinary metabolites may not occur for several days. Within 7 to 12 days, depending somewhat on age (see later), the melatonin cycle readjusts to the prevailing light–dark environment so that elevated levels coincide with the period of darkness. The interval required for reentrainment of the melatonin cycle also depends on the magnitude of the phase shift: the greater the phase shift, the greater the interval required for the melatonin rhythm to reentrain.
Nocturnal secretion of melatonin seems unrelated to sleep stage.12 Maximal plasma melatonin levels usually appear before the maximal rapid eye movement sleep peak.
In animals that experience natural photoperiodic and temperature conditions throughout the year, season has a significant influence on the plasma melatonin rhythm, affecting both the duration and the magnitude of the nocturnal rise.2 In humans, who live under more controlled environmental conditions, the influence of season is less obvious but may be measurable.13
AGE AND SEXUAL MATURATION
Age substantially influences the pattern of melatonin production (Fig. 10-4). Whereas the day–night periodicity in plasma melatonin levels probably is not present at birth, by the end of the first year of life children exhibit a robust rhythm.14 The highest nighttime levels of melatonin occur in children 1 to 5 years of age. Several reports document a significant attenuation of the nocturnal rise in plasma melatonin levels between 5 and 15 years of age (Fig. 10-5).15 This decrease is of particular interest because of its possible relationship to pubertal development. In animals, the activated pineal gland, or exogenous melatonin administration, can retard sexual maturation.16 Hence, the gradual decrease in nocturnal plasma melatonin levels as humans mature sexually may permit the establishment of adult neuroendocrinegonadal relationships.17

FIGURE 10-4. Changes in blood melatonin levels as a function of age. During the infantile period (age 0 to 1 year), the melatonin rhythm matures; after the first year of age, a decrease is seen in nocturnal melatonin levels. The drop in nighttime melatonin may be rapid (A and C) or gradual (B) from 5 to 15 years of age (immature period). Low nocturnal melatonin titers in advanced age may be a consequence of a gradual reduction (A and B) or associated with some critical event late in life (C).

FIGURE 10-5. Nocturnal serum melatonin values in male and female subjects aged 1 to 35 years. Values are plotted against chronologic age and state of sexual development (Tanner stages I to VI). Between 5 and 15 years of age, as individuals pass through puberty, nocturnal melatonin levels decrease by roughly 75%. (From Waldhauser F, Dietzel M. Daily and annual rhythms in human melatonin secretion: role in puberty control. Ann N Y Acad Sci 1985; 435:205.)

The decrease in nighttime melatonin levels in the decade beginning at 5 years of age has not been universally demonstrated. Even if a reduction in the ability of the pineal to secrete melatonin is correlated with pubertal onset, this does not mean that the indoleamine normally limits the maturation of the reproductive system. The case could be that gonadotropins or sex steroids secreted by the pituitary and gonads, respectively, inhibit the conversion of serotonin to melatonin in the pineal gland. Finally, the decrease in plasma melatonin may be merely a function of age and not causally related to the status of the reproductive organs. In one case report, however, a strong correlation was found between the decrease in circulating melatonin and pubertal onset.
After adolescence, most individuals continue to exhibit a 24-hour rhythm in plasma melatonin production and the urinary excretion of metabolites. In advanced age, however, the ability of the pineal to produce melatonin is severely limited, especially at night. In elderly persons, a nocturnal rise in melatonin is barely detectable.
AVERSIVE STIMULI
Aversive stimuli, which cause the release of large amounts of catecholamines into the systemic circulation, have been investigated for their effects on the discharge of melatonin from the pineal gland. In general, procedures such as electroconvulsive therapy, pneumoencephalography, and lumbar puncture, and conditions such as excessive short-term exercise, insulin-induced hypoglycemia, and psychologic conflict have a minor influence on day-time plasma melatonin levels.5 In one study, however, strenuous exercise in women significantly increased daytime circulating melatonin levels.18 The consequences of short-term rises in plasma melatonin during the day are unknown.
POSSIBLE SEX STEROID FEEDBACK
Several studies have described plasma melatonin levels as a function of the human menstrual cycle. The rationale for these studies was that, if melatonin has an antigonadotropic action in humans, as it has in some other mammalian species, then perhaps ovarian secretory products may limit pineal melatonin secretion at the time of ovulation. In some studies, nocturnal plasma melatonin levels were found to be lower during the midmenstrual cycle (ovulation) than during the postmenstrual or premenstrual periods.19 These results suggest that the midcycle lessening of the nocturnal melatonin increase may permit the release of pituitary gonadotropins required for ovulation. Not all investigators have reported menstrual cycle variations in the 24-hour melatonin rhythms, however. In acyclic athletic women, higher than normal circulating melatonin values have been reported.
Melatonin secretion has not been found to be linked to prolactin, growth hormone, adrenocorticotropin, testosterone, or luteinizing hormone.5
CLINICAL IMPLICATIONS
SEXUAL MATURATION
The pineal gland and melatonin have been implicated in several clinical entities.5 Besides the possible link between gradually decreasing nocturnal melatonin levels and pubertal development (see Fig. 10-5), pineal tumors may alter sexual maturation (also see Chap. 92).20,21 Tumors of the pineal gland are more prevalent in men than in women and may either retard or advance sexual development.20 The opposite responses to space-occupying lesions of the pineal region are explained on the basis of cellular origin (i.e., parenchymal or nonparenchymal) and the consequential endocrine capabilities of the tumorous mass. In addition, these tumors can cause increased intracranial pressure and, because of associated hydrocephalic dilation of the third ventricle, Parinaud syndrome (paralysis of upward gaze and slightly dilated pupils that react normally on accommodation but not to light) (Fig. 10-6). Hypermelatoninism with an enlarged pineal gland has been shown to be associated with delayed sexual development.

FIGURE 10-6. Computed tomographs (CTs) of a 67-year-old man with Parinaud syndrome and deteriorating mental status. Four years previously, the CT scan shown in A was obtained because of disorientation and dementia thought to be secondary to increased intracranial pressure. A 2-cm mass was seen in the pineal region (arrowheads) with triventricular dilation (arrow) (third and lateral ventricles). The fourth ventricle was not involved. The patient refused definitive surgery, and a ventriculoperitoneal shunt was performed. In the CT scan shown in B, the lesion has grown to 7 cm; the ventricles decreased in size considerably after shunt placement. (Courtesy of Dr. Frederick T. Borts.)

OVULATORY RELATIONSHIPS
The observation that nocturnal melatonin levels may be lowest at the time of ovulation in women suggests that a decrease in the indoleamine concentration may permit ovulation.19 In animals, exogenously injected melatonin can inhibit both the release of ova and the surge of ovulatory hormones associated with this process. Melatonin may have a similar antiovulatory capability in humans when given in pharmacologic doses.22 Higher than normal nocturnal melatonin secretion is associated with hypothalamic amenorrhea in women, and with delayed puberty.23
PSYCHOLOGICAL INTERRELATIONSHIPS
A possible link between various types of depression and pineal function has been proposed. Several psychiatric diseases have a strong seasonal component; one of these is seasonal affective disorder.24 This condition is characterized by recurring periods of depression during the winter months, when the natural day length is shortest. Typical symptoms are hypersomnia, excessive eating, a craving for carbohydrates, and sadness. Phototherapy for this disorder entails exposing the patient to bright (2500 lux), full-spectrum artificial light, usually early in the morning. The symptoms normally associated with seasonal depression are greatly reduced by phototherapy but are partially reinstated if melatonin is given orally during the period of phototherapy. Bright light early in the morning prevents the phase delay in the melatonin rhythm that may be typical of patients with seasonal affective disorder.
SLEEP
Persons given exogenous melatonin report feeling sleepy. Under usual conditions, high plasma melatonin levels are associated with the nightly sleep interval.25 Melatonin has been reported to affect brain levels of serotonin, a compound that may be important in the initiation or maintenance of sleep. In various studies, melatonin given orally or sprayed intranasally facilitated the onset of sleep or led to tiredness, and generally had a sedative effect. Melatonin is being touted as a sleep-enhancing agent, although the data is contradictory.25a
JET LAG AND OTHER BIOLOGIC RHYTHM DISORDERS
Jet lag has been related to elevated melatonin levels during times that the concentration of this indoleamine should be low.11 Flight across time zones is associated with a phase shift in the sleep–activity cycle. The circulating melatonin rhythm requires time to readjust, and during this interval melatonin levels are elevated or depressed at unusual times. This lack of synchrony is believed to be related to the fatigue associated with jet lag.26 Melatonin administration is being tested as a therapy for jet lag. The ability of melatonin to influence jet lag relates to its influence on the biologic clock (i.e., the suprachiasmatic nuclei). The neurons in these nuclei contain numerous receptors for melatonin.27 The membrane receptors on which melatonin acts are part of the superfamily of receptors that possess seven transmembrane domains. The receptors are pertussis toxin sensitive and G-protein linked. Cyclic adenosine monophosphate (cAMP) functions as the intracellular messenger.28
TUMOR GROWTH
The possibility that the pineal gland and melatonin may be related to tumor growth has received much attention.29 The interactions of the pineal gland with tumor promotion are most obvious in the case of malignant growths that are dependent on sex steroids or prolactin. In addition, because of its free radical scavenging ability (see later), melatonin may prevent DNA damage that precedes tumor initiation.
Depressed nocturnal plasma melatonin levels in patients with mammary cancer may contribute to tumor growth. In pre-menopausal and postmenopausal women with clinical stage I and II mammary carcinogenesis, the nocturnal melatonin rise was attenuated in those with estrogen receptor–positive tumors, compared to those with estrogen receptor–negative mammary growths.30 In the patients with estrogen receptor–positive tumors, a strong negative correlation was seen between plasma melatonin concentrations and estrogen receptors in the tumor. Whether the lower levels of melatonin in these women were a cause or an effect of the tumor, or an unrelated temporal association, was impossible to determine. Melatonin is known to suppress cellular proliferation and tissue growth.29
FREE RADICAL SCAVENGING
Melatonin has been shown to be a highly effective scavenger of the hydroxyl radical, singlet oxygen, and the peroxynitrite anion, and it stimulates the activity of several antioxidative enzymes.31 Because of its multiple antioxidative actions, melatonin has been tested for its ability to reduce oxidative damage due to ionizing radiation and a variety of xenobiotics; in these tests pharmacologic levels of melatonin have been shown to efficiently abate oxidative damage.32 These findings have generated interest in the potential use of melatonin in the treatment of neurodegenerative diseases of the aged that may involve free radical damage to neurons.31,33 Examples of such conditions include Alzheimer, Parkinson, and Huntington diseases.
CONCLUSION
The human pineal gland is a highly active organ that secretes at least one indole hormone, melatonin, and possibly several other active substances, either indoleamines or peptides. Assays are available to measure melatonin in bodily fluids34 and its metabolites in the urine. The cyclic production of melatonin is highly characteristic, with highest levels occurring during the dark/sleep phase. The consequences of altered melatonin rhythms are incompletely understood but likely relate to several clinical entities. In addition, some persons probably have an excess (hypermelatoninism)17 or deficiency (hypomelatoninism)35 in melatonin production and secretion.
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