Melatonin

2 H A P T E R .5{

Melatonin RALF C. ZIMMERMANN

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Columbia University College of Physicians and Surgeons, New York, NY 10032

JAMESM. OLCESE Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306

I. CHEMISTRY, SYNTHESIS, AND METABOLISM

produces the hormone melatonin. Melatonin, which is lipophilic and hydrophilic, can leave and enter cells by simple diffusion. It is transported in the blood in an albuminbound form and cleared quickly (half-life less than 40 minutes). Melatonin (see Fig. 58.1) (see color insert) is metabolized in the liver to 6-hydroxymelatonin, which undergoes conjugation to either sulfate or glucuronide and is excreted mainly into urine (6). The enzyme arylalkylamine N-acetyltransferase controls the daily rhythm in pineal melatonin production and blood melatonin concentration. The activity of this enzyme increases substantially at night in the absence of light but is inhibited in the presence of light (6). Regulation of the expression of this gene occurs through [31-receptors, which are located in the membrane of pinealocytes. Binding of norepinephrine or a compound with ~-agonist activity will stimulate a Gstimulatory protein complex, which via adenylyl cyclase will produce cyclic adenosine monophosphate (cAMP), which will activate cAMP-dependent protein kinase to phosphorylate, a cAMP response element binding protein (CREB), to form phosphorylated CREB. It is likely that this process might be enhanced by norepinephrine's action on the ]31-adrenergic receptor located in the membrane of pinealocytes. The night-day ratios of pineal AANAT mRNA varies from more than 150:1 in the rat to 1.5:1 in sheep. Tissuespecific AANAT mRNA expression in the human is high in the pineal gland and retina, low in other areas of the brain,

The indole derivative N-acetyl-5-methoxytryptamine, which is better known as melatanin, was discovered by Lerner et al. (1) in 1958. This hormone is mainly synthesized by pinealocytes located in the pineal gland (2,3). The pineal gland is a small cone-shaped structure attached to the roof of the third ventricle between the superior colliculi, immediately adjacent to the habenular commissure (Fig. 58.1) (see color insert) (4). Melatonin is produced from the essential amino acid tryptophan, which is taken up by the gland passively from the bloodstream. Blood tryptophan shows a circadian rhythm (5), which very likely does not influence melatonin production as the concentration of the melatonin precursor 5-hydroxytryptamine in the pineal gland is high (6). Tryptophan is converted to 5-hydroxytryptophan in a reaction catalyzed by the enzyme tryptophan hydroxylase. The next step in melatonin production is the decarboxylation of 5-hydroxytryptophan by an L-amino-decarboxylase, which converts it to 5hydroxytryptamine, better known by the name serotonin. Serotonin is then converted to L-acetyl-5-hydroxytryptamine by an arylalkylamine N-acetyltransferase (AANAT), the rate-limiting step. This enzyme, which has been cloned, plays a key role in the regulation of melatonin production [7). The human AANAT gene is located on chromosome 17@5. O-methylation of N-acetyl-5-hydroxytryptamine TREATMENT OF THE POSTMENOPAUSAL WOMAN

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FIGURE 58.1

Regulationof melatonin secretion. (From res 97, with permission.)

and undetectable in peripheral tissues (7). It is of note that repeated stimulation of the pinealocyte with norepinephrine does not tonically elevate AANAT activity or AANAT mRNA. Therefore, stimulation of [31-receptors seems to induce a second mechanism, which counteracts AANAT activity. Inducible cAMP early response element (ICER) appears to function as such an inhibitory factor (8).

II. R E G U L A T I O N OF MAMMALIAN PINEAL MELATONIN RHYTHM AND

DETECTION

IN BLOOD

The rhythm of pineal melatonin secretion is regulated by a well-characterized neural circuit that drives the activity of pinealocytes to produce and secrete melatonin (9). Circadian stimulatory signals originate in the suprachiasmatic nucleus (SCN) (see Fig. 58.1) (see color insert), the principal circadian pacemaker in the mammalian brain; they are transmitted to the pineal gland through the hypothalamic paraventricular nucleus via the medial forebrain bundle to the intermediolateral cell column of the upper spinal cord, which in turn innervates the superior cervical ganglia (9). These ganglia innervate the pineal gland with norepinephrine-containing fibers. Release of this neurotransmitter increases AANAT mRNA, as described earlier (10). The SCN is the circadian pacemaker that is not dependent on the dark-light cycle, but rather functions autonomously. Input or entrainment path-

ways establish the precise period and phase of the pacemaker (i.e., it assures appropriate adjustment to the 24-hour lightdark cycle). Light, an entrainment signal (Zeitgeber), acts through the retino-hypothalamic pathway (see Fig. 58.1) (see color insert) to reset the clock (SCN), and via the SCN it makes subtle adjustments in the duration and intensity of stimulation of the pineal gland and its output signal melatonin. Blind individuals with abnormal retinal processing or a defective retino-hypothalamic tract can have free-running rhythms (11). The power of the input signal light in altering SCN activity and its impact on the pineal gland and melatonin secretion are exemplified by the following example: Light exposure at a time of high melatonin secretion, such as nighttime, blocks the SCN/pineal gland transmission, thereby terminating norepinephrine release into the pineal extracellular space, which promptly lowers melatonin production and release (12,13). Blood melatonin concentration is low during the daytime (20 to 25 pmoL/L), and increases at night with peak levels between 2 AM and 4 AM of 150 to 200 pmoL/L (1 pg/mL = 4.31 pmoL/L) (14). A similar pattern is seen when metabolites of melatonin are measured in urine; for example, 24-hour urine measurements of 6-hydroxymelatonin sulfate reflect 24-hour plasma melatonin secretion adequately (15). Melatonin production or secretion is not influenced by gender. Wide interindividual variation in melatonin secretion is seen, but the intraindividual secretion pattern is relatively stable (16,17). As mentioned, blind people whose retina is no longer competent to inform the SCN about light and darkness through the retinohypothalamic tract still secrete melatonin in a circadian

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fashion, but this secretion might no longer be entrained to light (i.e., the rhythm is free running). This is one of the reasons why these individuals might suffer from sleep-related problems (11).

III. MELATONIN RECEPTORS AND EFFECTS OF MELATONIN ON THE SUPRACHIASMATIC NUCLEUS Following the introduction of 2-(1251) iodomelatonin analogs, specific melatonin receptors were identified in the SCN but not in the pars mberalis of the pituitary gland in the human (18,19). Melatonin receptors, which have also been identified in the brain including the preoptic area, cerebral cortex, and thalamus of some mammals, could mediate the hypnotic effects of this hormone (20). Melatonin receptors in non-neuronal tissue are found in cerebral arteries, renal tubular cells, ovarian granulosa cells, uterine myometrium, Leydig cells of the testis, and prostate epithelial cells (6,21). The physiologic significance of these receptors in non-neuronal tissue is currently not clear. The dissociation constant (Kd) of this receptor is less than 100 pM (i.e., it is physiologically meaningful). The human melatonin receptors have been cloned by molecular biologic techniques (20,22). At least two receptor subtypes, MT1 and MT2, are coupled to Ginhibitory proteins. The chromosomal locations are 4q35.1 and 11q21-22, respectively (20). It has been shown recently that MT1 involves both inhibition of adenylyl cyclase and potentiation of phospholipase activation (23). Melatonin binding leads to a functional change in the SCN. SCN, cultured in vitro, continues 24-hour oscillations, with neuronal firing being maximal corresponding to the light phase and the firing being minimal corresponding to the dark phase of animals before sacrifice (24). The acute inhibitory activity of melatonin on neuronal firing seems to be mediated through activation of potassium channels activated by the f3y subunits or pertussis toxin-sensitive G proteins, which is consistent with melatonin signaling through Ginhibitoryproteins (24). This acute suppressive effect of melatonin on SCN multi-unit firing is abolished in MT1 receptor-deficient mice (24). In vitro application of physiologic melatonin concentrations to the SCN at specific time points can reset the neuronal circadian rhythms (25). Phase shifting activity by melatonin to reset the SCN is greatest prior to the onset of darkness, with robust advances of 2 to 4 hours occurring in subsequent melatonin rhythms (25). The phase shifting effect of melatonin, which is distinct from the acute inhibitory effect of melatonin on neuronal firing, might involve protein kinase C (26) and nitric oxide (27). This effect may be mediated by the MT2 receptor, as receptor knock-out mice (24) continue to show the phase shift phenomenon in response to melatonin despite the lack of MT1

receptors. Therefore, multiple signaling pathways might be used by the two melatonin receptors for different physiologic effects on the SCN. Detection ofmelatonin receptor-mediated alterations in gene expression, which might mediate these distinct effects ofmelatonin on the SCN, has recently begun to be analyzed (6). The expression of melatonin receptors is a dynamic process that might show a circadian variation in their binding capacity, as is exemplified in the SCN. Maximal binding of 125I-iodomelatonin to rat SCN melatonin receptors occurs late in the day and minimal binding in early morning around 4 AM (28). Gauer et al. (28) speculated that daily variations in plasma melatonin concentrations could be implicated in the regulation of the density of melatonin binding sites in the SCN and pars mberalis, possibly by a mechanism of desensitization of the melatonin binding sites by melatonin itself. If this is correct, administration of high doses of melatonin might not be innocuous as this could downregulate its own melatonin receptors. Also based on the observations discussed earlier (24,25), timing of exogenously administered melatonin might be crucial to cause a shift in circadian rhythms.

IV. PHYSIOLOGIC AND PATHOPHYSIOLOGIC ASPECTS OF MELATONIN SECRETION

A. Physiology In a natural setting, entrainment by melatonin may be most important during early development when retinamediated light information cannot be processed (29). Maternal melatonin secretion rhythms are maintained during pregnancy (30). During fetal life, at a time when the retina-SCN pathway has not yet formed, melatonin produced by the mother provides the developing SCN with entraining information. This fetal-maternal information keeps the fetal clock entrained and in rune with the outside world until the retinamediated entrainment becomes functional during postnatal life (29). Babies up to the age of 3 months do not have a welldeveloped circadian rhythm (31). Nighttime melatonin secretion peaks during early childhood and then drops sharply until early adulthood (32). It has been speculated that the sharp decline in melatonin secretion that occurs in late childhood might be involved in the initiation of puberty, but no strong data are available to support this assumption. Melatonin continues to decrease significantly with age; similarly, the time during which melatonin remains elevated at night also decreases with age (33). Studies in women during the perimenopause reveal that the decline in melatonin precedes follicle-stimulating hormone increase during menopause, with a decline of 41% in the age group 40 to 44 years and a

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further decline of 35% between the age groups 50 to 54 years and 55 to 59 years (34). Whether this decline in melatonin secretion contributes to the development of menopause or to menopausal symptoms and signs is questionable. An association between the quality of sleep and the amount of melatonin secreted has been noted, especially in the elderly (35). Animal studies that included mice whose ovaries no longer functioned (similar to menopause) seemed to show that the aging process could be slowed down by the pineal grafting of young pineal glands from young animals onto aging animals. It was speculated that this inhibitory effect on aging might possibly be mediated by melatonin (36). Obviously, if these findings could be replicated, this would have important consequences in the management of menopause and aging (see later discussion). Body temperature fluctuates during the 24-hour time period, with temperature being higher during the daytime when compared with the nighttime. The drop in nighttime temperature can be reversed by exposure to bright light. Because this effect is mediated by melatonin, this hormone decreases core body temperature (37,38). The temperaturelowering effect of melatonin might of therapeutic interest because hot flushes are associated with an increase in temperature. No studies are available to answer this question. Melatonin secretion changes with alterations in the length of daytime encountered in the different seasons of the year. This has powerful effects on reproductive function in seasonal breeding animals, but if present, its effect on human reproduction seems to be minimal (39,40). Melatonin secretion does not change in different phases of the menstrual cycle or with the administration of oral contraceptives (14,17). Melatonin receptors have been identified in human granulosa cells (41), and this hormone stimulates progesterone production by human granulosa cells (42). Also, melatonin seems to concentrate in follicular fluid (43). The physiologic significance of these observations is not clear. A possible association of 24-hour melatonin secretion pattern and the initiation of the luteinizing hormone (LH) surge have been observed (43,44).

B. Pathophysiology Nocturnal melatonin secretion is amplified in women with functional hypothalamic amenorrhea (45,46). It is not clear whether increased melatonin concentration is a contributing factor in causing amenorrhea by influencing LHreleasing hormone secretion or is an epiphenomenon. Shortterm administration of supraphysiologic doses of melatonin (60 to 300 mg), which created supraphysiologic levels in the periovulatory, period did not prevent ovulation (44,47). Long-term use of high-dose melatonin (4 months, 300 mg/ day) seems to decrease the midcycle LH surge. It has been suggested that a combination of high-dose melatonin with a

OLCESE

progestin derivative (norethindrone) could be used as an estrogen-free oral contraceptive pill (47). Acute elevations of melatonin occur during fasting (48) and sustained exercise (49). The importance of these observations regarding possible impact on reproduction currently is not clear. Traveling across several time zones creates a situation in which the body's circadian rhythms, including melatonin secretion, are temporarily not properly synchronized to the prevailing light-dark cycle, which might cause jet lag (50). While readjusting their circadian rhythm to local time, individuals experience difficulty sleeping, among other signs and symptoms. Chronic circadian disturbance as encountered in shift work might cause many of the health and social problems reported by shift workers, including chronic sleep problems.

V. COMPOUNDS THAT ALTER MELATONIN SECRETION Because alterations in melatonin secretion might have an impact on the circadian rhythm and possibly sleep, it is important to be aware of substances that influence melatonin secretion. Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin or ibuprofen) can lower melatonin secretion. These medications interfere with the production of prostaglandins, which can influence melatonin production in the pinalocyte (51). As would be expected from the regulation of melatonin secretion, [3-blockers (e.g., atenolol) abolish the nocturnal rise of melatonin secretion (15). Similarly, presynaptic blockage of norepinephrine production with cx-methyl-para-tyrosine attenuates the nocturnal melatonin peak (52). It is of note that subjects taking this compound complain of sleep disturbances for several days after stopping medication, which could be related to the disruption of the circadian rhythm of melatonin secretion. Some of the calcium channel blockers and the el2 receptor agonist clonidine decrease melatonin secretion (53,54). Decreased intracellular Ca 2+ levels seem to interfere with melatonin production, and presynaptic cx2 receptors decrease norepinephrine release. The sedative-hypnotics of the benzodiazepine type (e.g., diazepam and alprazolam), which act on the ~/-aminobutyric acid complex type A receptor complex, lower melatonin secretion (55,56). Antidepressants such as the norepinephrine reuptake inhibitor desipramine and monoamine oxidase (MAO) inhibitors seem to increase plasma melatonin secretion (57,58). Serotonin reuptake inhibitors can increase or decrease melatonin secretion (59,60). Therefore, different types of antidepressant medication might interfere with the circadian rhythm or magnitude of melatonin secretion. Caffeine and alcohol might decrease melatonin secretion, especially when consumed at nighttime (61,62). Dexamethasone decreases melatonin secretion (63). Alterations in plasma tryptophan concentration can increase or decrease melatonin secretion (64,65).

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VI. THERAPEUTIC INTERVENTIONS USING MELATONIN

A. Circadian Rhythms Jet lag is caused by traveling across several time zones within several hours. The internal clock (i.e., the SCN) is not synchronized with the daytime-nighttime rhythm at the place of arrival. Jet lag can cause insomnia, fatigue, irritability, and poor concentration. It is easier to adapt when flying west, when the day is stretched, than flying east when the day is compressed. A possible explanation is that the body clock operates on a 25-hour rhythm when no clues are given to the SCN (66). To alleviate jet lag symptoms, it is recommended to take low doses of melatonin I to 2 hours prior to going to bed in the place of destination for several days (67,68). In addition to other environmental clues, such as light, melatonin helps to reset the clock faster. Taking melatonin at a time corresponding to the beginning of the sleep period at the point of destination, starting a few days prior to departure, can inconvenience people significantly because of side effects such as drowsiness. Most of the data available seem to demonstrate that starting treatment after arrival seems to produce similar positive results when compared with starting to take melatonin several days prior to departure (69). Therefore, it is recommended to take a dose of 0.5 mg of melatonin I to 2 hours before bedtime after arrival at the destination (66,67,69). Exposure to sunlight after arrival also might help to reset the SCN (70). When traveling more than six time zones, avoiding bright light exposure at certain times might become important in facilitating readaptation, and a nomogram has been developed that helps to avoid exposure at these critical periods (71,72). A recent meta-analysis questioned the beneficial effect of treatment with melatonin for jet lag (73,74).

B. Shift Work Switching from working during the daytime to working at night is very taxing as the sleep-wake cycle is opposite to the light-dark cycle of the environment. A recent study on night workers (75) demonstrated that workers with an altered melatonin rhythm had a higher prevalence of sleep disorders, fatigue, and mental symptoms, as compared with workers with normal melatonin rhythms. To improve adjustment to these conditions, workers can expose themselves to artificial bright light at night, which resets the SCN and lowers melatonin levels (76-78). In addition, avoiding exposure to bright light during the daytime and taking melatonin (0.5 to 5 mg) or melatonin agonists such as agomelatine (79) prior to sleep seems to improve daytime sleep and alertness (66,77,80). It is not clear how beneficial an attempt to shift

the sleep-wake cycle is in the short term (--- 4 weeks). It is of note that air travelers do adjust their circadian rhythm faster than shift workers. Melatonin production that prevents the desired shift is suppressed by sunlight exposure, which is generally much brighter than the indoor light exposure for shift workers. Sunlight is also available to help shift the endogenous circadian pacemaker (70). A recent meta-analysis questioned the beneficial effect of treatment with melatonin for shift work (73,74).

C. Sleep Disturbances Sleep disturbances increase with age. Possible reasons for the high frequency of sleep complaints in elderly people are primary endogenous, age-related sleep disorders; increased likelihood of disease that interferes with sleep; and drug use, which can cause secondary sleep disorders (81). Therefore, it is important to review nonprescription and prescription drugs used should be reviewed before beginning treatment with melatonin in patients with insomnia due to physical disorders, mental health problems including depression and anxiety disorders, improper sleep environment, inadequate sleep habits, circadian cycle abnormalities, and substance abuse (82). It might also be prudent to collect nocturnal urine, preferably in 3-hour intervals, to detect a decrease in melatonin secretion or a shift in its peak secretion (81). To document improvement, a subjective sleep diary should be kept and if possible an actigraph should be used to estimate sleep variables (sleep quality, etc.) during melatonin use. Because of the rapid metabolism of orally administered melatonin, slow-release capsules as the one used by Garfinkel et al. (81) might be preferable (2 mg, Circadin, Neurim Pharmaceutical, Tel Aviv, Israel). Wurtman and Zhdanova (83) had similar positive results in sustaining sleep in elderly insomniacs using an oral dose of melatonin (0.3 mg). More recently the melatonin agonist ramelteon (Rozerem), a selective M T I / M T 2 receptor agonist, was approved by the Food and Drug Administration (FDA) for the treatment of insomnia (84). Therefore, in a carefully screened group of patients suffering from insomnia, a trial of melatonin might be indicated before switching to more powerful medications such as benzodiazepines, which have more side effects. Patients suffering from delayed sleep phase syndrome might possibly benefit from melatonin treatment (79,85). The effectiveness of melatonin in the treatment of secondary sleep disorders has been questioned in a recent meta-analysis (73,74).

D. Unproven Benefits from Melatonin Melatonin secretion can be decreased in patients with psychiatric disorders, especially depression (86). Some forms of depression seem to involve dysregulation in the

834 central nervous system of norepinephrine- and serotonincontaining neurons and their receptors (87,88). Therefore, at least from a theoretic standpoint, an attractive hypothesis is that alterations in melatonin secretion reflect disease states as both systems play an important role in the regulation of melatonin secretion (52,89). Unfortunately, no consistent changes in melatonin secretion have been found that reflect depression (32,89). Therefore, melatonin measurements cannot be used to diagnose depression, and treatment of depression with melatonin is not appropriate. Seasonal affective disorder, which is characterized by recurrent episodes of depression, hypersomnia, and augmented appetite in the autumn and winter, fulfills the criteria of a rhythm disorder (90). These patients show a change in core temperature rhythms, but melatonin rhythm and amplitude seem to be unchanged (90). The preferred therapy is timed exposure to bright light, and it is not clear whether melatonin administration might beneficial to this group of patients (90). Melatonin secretion does not seem to be altered in women with premenstrual syndrome (91). Patients suffering from anorexia nervosa might have elevated melatonin blood levels, but this has no therapeutic implications (92). Administration of 3 mg melatonin at bedtime to perimenopausal and postmenopausal women has been reported to improve thyroid function, causes a change of gonadotropins toward more juvenile levels, and might have some antidepressive activity (93,94). Use of melatonin alone for the relief of menopausal symptoms, including hot flushes, does not seem to be effective (95). In very high pharmacologic doses, melatonin works as an antioxidant, possibly through non-receptor-mediated mechanisms. It has been claimed that this property of melatonin might have a preventive effect on illnesses affected by free radicals (66). As stated by Reppert and Weaver (29), this antioxidant effect requires melatonin concentrations approximately 100 times greater than the physiologic melatonin secretion (1 nM). Therefore, an antioxidant effect of melatonin may have some therapeutic application, but definitely not to the extent claimed in self-help books (66). It has also been claimed that melatonin can reverse aging (96). Some researchers have studied strains of mice with a well-described genetic defect in pineal melatonin biosynthesis, which therefore could not make melatonin (29,36). In some of these melatonin-deficient mice strains, life span increased by 20%, but not in female C57BL/6 mice. The life span was actually shortened in the mouse strain C3H/He secondary to reproductive tract tumors (29,36). Thus, no evidence indicates that melatonin administered to melatoninproducing mice can increase longevity. The suggestion that melatonin may increase longevity in humans is based on pure speculation (29).

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VII. SUMMARY Molecular biology has been able to disperse some of the myths surrounding melatonin. Melatonin production sites can be clearly identified by detecting message and protein from AANAT in specific tissues. Specific melatonin receptors have been identified by detecting message and protein in specific tissues. Activation of specific signaling pathways used by different melatonin receptors can be detected. Also, knock-out models will help to further clarify the physiologic action of this hormone as well as its pathophysiologic states. This grounding in molecular biology will help to develop sound therapeutic applications for melatonin. It would be regrettable if melatonin did not find its proper place in the therapeutic armamentarium, given the well-defined positive actions of this fascinating hormone. References 1. Lerner BA, et al. Isolation of melatonin, pineal factor that lightens melanocytes.Jdm Chern Soc 1980;80:2587. 2. Cardinali DP. Melatonin. 1. A mammalian pineal hormone. Endocr Rev 1981;2:327-346. 3. Reiter RJ. The pineal and its hormones in the control of reproduction in mammals. Endocr Rev 1980;1:109-131. 4. Preslock JP. The pineal gland: basic implications and clinical correlations. Endocr Rev 1984;5:282-308. 5. Krahn LE, Lu PY, Klee G, et al. Examining serotonin function: a modified technique for rapid tryptophan depletion. NeuroDsychopharmacology 1996;15:325-328. 6. Olcese J. Cellular and molecular mechanisms mediating melatonin action. Aging Male 1998;1:113-129. 7. Klein DC, Roseboom PH, Coon SL. New light is shining on the melatonin rhythm enzyme. The first postcloning view. T E M 1996;7: 106-112. 8. Coon SL, Mazuruk K, Bernard M, et al. The human serotonin N-acetyltransferase (EC 2.3.1.87) gene (AANAT): structure, chromosomal localization, and tissue expression. Genomics 1996;34:76- 84. 9. Moore RY. Neural control of the pineal gland. Bebav Brain Res 1996; 73:125-130. 10. Roseboom PH, Coon SL, Baler R, et al. Melatonin synthesis: analysis of the more than 150-fold nocturnal increase in serotonin N-acetyltransferase messenger ribonucleic acid in the rat pineal gland. Endocrinology 1996;137:3033- 3045. 11. Lockley SW, et al. Relationship between melatonin rhythms and visual loss in the blind.d Clin EndocrinolMetab 1997;82:3763-3770. 12. Bispink G, et al. Influence of melatonin on the sleep-independent component of prolactin secretion, d Pineal Res 1990;8:97-106. 13. Lewy AJ, et al. Light suppresses melatonin secretion in humans. Science 1980;210:1267-1269. 14. Berga SL, Yen SS. Circadian pattern of plasma melatonin concentrations during four phases of the human menstrual cycle. Neuroendocrinology 1990;51:606-612. 15. Arendt J, et al. Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab 1985;60:1166-1173. 16. Arendt J. Radioimmunoassayable melatonin: circulating patterns in man and sheep. Prog Brain Res 1979;52:249-258.

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