The pineal gland is a small organ (150 mg in humans) located near the center of the brain. One of the major components of the mammalian circadian system, it lies in the upper margins of the thalamus in the dorsal aspects of the third ventricle and has both physical and neuronal connections with the brain. Although the pineal gland lies outside the blood-brain barrier, it has access to the cerebrospinal fluid. The pineal gland’s major neuronal connections with the brain are the sympathetic nerve fibers coming from the superior cervical ganglion; the activity of these sympathetic nerves controls synthesis and release of the pineal hormone melatonin (Cone et al. 2002).11 Other substances (primarily peptides) are also secreted from the pineal gland and have been reported to have various physiological effects, including antigonadotropic, metabolic, and antitumor activity (Anisimov 2003).

Most melatonin production occurs during darkness (Reiter 1998; Salti et al. 2000; Cone et al. 2002; Murcia García et al. 2002). Peak serum concentrations of melatonin occur during childhood in humans, with decreasing concentrations during adolescence before stabilization at the low concentration characteristic of adults (García-Patterson et al. 1996; Murcia García et al. 2002); further decreases in melatonin occur at menopause in women and at a corresponding age in men (Reiter 1998).

Melatonin affects target tissues, such as the hypophyseal pars tuberalis, that have a high density of melatonin receptors. The primary effect seems to be temporally specific activation of cAMP-sensitive gene expression in the pars tuberalis by the sensitization of adenylyl cyclase, thus synchronizing the suprachiasmatic nucleus of the hypothalamus and clock-controlled genes in peripheral tissue (Stehle et al. 2003). In humans, changes in melatonin are associated with the status of the reproductive system—onset of puberty, stage of puberty, menstrual cyclicity, menopause (Reiter 1998; Salti et al. 2000)—but the functional relationships are not fully understood. The elevated melatonin concentrations characteristic of prepubertal age suggest an inhibitory effect on pubertal development (Aleandri et al. 1997; Salti et al. 2000); sexual maturation begins when serum melatonin starts to decrease (Aleandri et al. 1997; Reiter 1998). Melatonin also seems to be involved with anxiety reactions; for example, the beneficial effects of fluoxetine (Prozac) in mice during an anxiety test are not found if the pineal gland has been removed (Uz et al. 2004).

Melatonin and pineal peptides have been associated with a number of other physiological effects, including regulation of circadian rhythms and


Melatonin is also found in cells lining the gut from stomach to colon. Its functions are mainly protective, including free radical scavenging. Some of melatonin’s actions are receptor-mediated and involve the central and peripheral sympathetic nervous systems (Reiter et al. 2003a).

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