Melatonin production and the pineal gland's regulatory functions

Melatonin & the Pineal Gland

The focus of this work is to examine melatonin and the pineal gland. Towards this end, this study examines the literature in this area of study and reports on the findings. The work of Turgut and Kumar (1996) addresses information on the pineal gland, "epiphysis…a small gland in the brain. Stated as that the chief product of pineal gland is that of melatonin. Aleandri, Spina and Morini report that the pineal gland hormonal activity "is influenced by both the dark-light cycle and the seasonal cycle, causing it to play an important role in the neuroendocrine control of reproductive physiology."

Melatonin & The Pineal Gland

The work of Turgut and Kumar (1996) addresses information on the pineal gland, "epiphysis…a small gland in the brain. Stated as that the chief product of pineal gland is that of melatonin. Aleandri, Spina and Morini report that the pineal gland hormonal activity "is influenced by both the dark-light cycle and the seasonal cycle, causing it to play an important role in the neuroendocrine control of reproductive physiology." This is reported to be "especially evidence in seasonal breeding animals, in which reproductive function is clearly influenced by seasonal variations in the duration of night and day." (1996, p.225) Aleandri, Spina and Morini additionally stated that the pineal gland's important was realized in the 16th century when it was believed to be the "seat of the soul." (1996, p.225)

II. Functions of the Pineal Gland

Arendt (2003) writes that the pineal gland from all appearances serves the same function in all mammals studied to date. The report states that the pattern of secretion of the major hormone, melatonin, "conveys information concerning light-dark cycles to the body physiology for the organization of seasonal and circadian rhythms." (p.1) Arendt states additionally "The pineal gland is part of the visual system and mammalian pinealocytes are derived evolutionarily from the pineal photoreceptors of lower vertebrates. The in-uence of the pineal gland on the circadian system appears to be more important in lower vertebrates than in mammals. In some reptiles and birds, the pineal appears to act as a central circadian rhythm generator. " (2003) Reported as well is the following information:

"In house sparrows (Passer domesticus), pinealectomy leads to arrhythmicity which can be restored by transplanting a pineal from another bird (Menaker et al., 1981). The circadian phase of the donor bird is conveyed to the host with the transplant. It is possible to culture pineal explants and dispersed pineal cells from ?sh, lizards and birds, and these preparations retain their circadian melatonin production in vitro. In contrast, the mammalian pineal does not retain endogenous rhythmicity in culture. The retina of lower vertebrates also generate melatonin rhythms in culture and the hamster retina (maintained at low temperature; Tosini and Menaker, 1996) can show the same phenomenon, which suggests that there may be a circadian pacemaker in the mammalian eye." (p.13) Arnedt reports that melatonin is synthesized within the pineal gland itself, in the retina and possibly in some other sites" but it is stated that in mammals, the majority and in some cases all of the hormone reaching peripheral sites is "derived from the pineal and pinealectomy leads to a great reduction and in the majority of cases in concentrations that cannot be detected in melatonin circulation. Arnedt reports that melatonin is synthesized from "tryptophan via 5- hydroxylation by tryptophan-5-hydroxylase to 5-hydroxytryptophan, decarboxylation by aromatic aminoacid decarboxylase to 5-hydroxytryptamine (serotonin), Nacetylation by N-acetyl transferase to N-acetylserotonin (NAT) and O-methylation by hydroxyindole-O-methyltransferase (HIOMT) to melatonin (N-acetyl-5-methoxytryptamine)." (Arendt, 2003)

It is reported that the primary feature of the synthetic pathway is "its rhythmicity." The activity of the NAT enzyme is stated to increase "from 30-fold to 70-fold at night, and in some circumstances is rate-lmiting in melatonin synthesis." (Arendt, 2003)

The Fluoride Action Network states that no research had been dedicated to examine the pineal gland's reaction to exposure to fluoride. The study findings note that the pineal gland is "the primary target of fluoride accumulation within the body." (2012) The pineal gland is comprised of soft tissue in an adult and is stated to contain "more fluoride than any other soft tissue in the body and in fact a level stated at "~300 ppm [is] capable of inhibiting enzymes. Also comprising part of the pineal gland is hard tissue" which is reported as accumulating "more fluoride (up to 21,000 ppm) than any other hard tissue in the body (e.g. teeth and bone)." (Fluoride Action Network, 2012, p.1)

It is reported that an experiment was conducted for the purpose of determining if accumulated fluoride might affect the functioning of the pineal gland and specifically if the gland's regulation of melatonin would be affected. Conclusions of the study report "… the human pineal gland contains the highest concentration of fluoride in the body. Fluoride is associated with depressed pineal melatonin synthesis by prepubertal gerbils and an accelerated onset of sexual maturation in the female gerbil. The results strengthen the hypothesis that the pineal has a role in the timing of the onset of puberty. Whether or not fluoride interferes with pineal function in humans requires further investigation." (Fluoride Research Network, 2012, p.1)

Bowen (2003) writes that the pineal gland serves to communicate information about the environmental lighting to parts of the body and that melatonin has the capacity to "entrain biological rhythms and has important effects on reproductive function of many animals. The light-transducing ability of the pineal gland has led some to call the pineal the 'third eye'." (p.1) Bowen states that serotonin is a neurotransmitter that is "derived from the amino acid typotophan and is a precursor of melatonin. Serotonin is stated to be acetylated in the pineal gland and to then be "methlyated to yield melatonin. This is illustrated as follows which has been adapted from the work of Bowen.

Figure 1

It is noted that the eyes receiving light exposure serves to dramatically impact synthesis and secretion of melatonin and it is stated that the "fundamental patterns observed is that serum concentrations of melatonin are low during the daylight hours and increase to a peak during the dark." (Bowen, p.1)

Stated as examples of the circadian rhythm in melatonin secretion in humans is that illustrated in the following figure in which dark gray is representative of night and serum melatonin levels displayed for two individuals (light blue vs. yellow). The blood levels of melatonin are not detectable during daylight hours however, these levels experience a sharp rise in nighttime hours. The melatonin secretion duration daily is reported as "directly proportional to the length of the night." (Bowen, 2003, p.1)

Figure 2

Examples of the Circadian Rhythm in Melatonin Secretion in Humans

Source: Bowen (2003)

The work of Buscemi, et al. (2004) reports a study by the Agency for Healthcare Research and Quality (AHRQ) stated to be developing scientific information and other organizations on which they can base clinical guidelines, performance measures and other quality improvement tools." (p.1) It is reported that it is indicated in studies that sleep disorders impact approximately 50 to 70 million Americans or 20% of the population. A sleep disorder exists when the individual has a "lower quality of sleep [resulting] in impaired functioning or excessive sleepiness. Insomnia, literally "inability to sleep," has various etiologies and is the most common sleep disorder, affecting between 6 to 12% of the adult population. In addition to the adult population, difficulties initiating and maintaining sleep are very common in children, affecting about 15 to 25% of this population." (Buscemi, et al., 2004)

Buscemi et al. reports a study that reviewed the utilization of melatonin for sleep disorder treatment. Biomedical databases were included in the information researched with literature searches reported as being "limited to English-lanugae reports of studies on human subjects with no age, gender or ethnicity restrictions. Reports of Clinical 1, Clinical 2, or Clinical 3 randomized clinical trials, quasi-randomized controlled trials, prospective cohorts, case series, registry data as well as narrative and systematic reviews." (2004) Buscemi et al. (2004) states that the data "were extracted from all reports of studies that were included in the review using a standardized Data Extraction Form." (Buscemi, et al., 2004) Included in the report are specifics as follows:

(1) Details of study design and inclusion/exclusion criteria.

(2) Details of the population such as gender, age, ethnicity, and type of sleep disorder.

(3) The number of individuals that were eligible for, and enrolled in, the study.

(4) The number of comparison groups and participants allocated to each group.

(5) The number of participants who withdrew from the study.

(6) Details of the intervention such as the formulation, dosage, timing, frequency and duration of melatonin administration as well as the type and frequency of usage of concurrent medication.

(7) Results obtained for predetermined, question-specific outcomes. (Bucemi, et al., 2004)

Key observations noted in the literature review conducted by Buscemi et al. On the effectiveness of exogenous melatonin in normal sleepers are those stated as follows:

(1) Effectiveness of Exogenous Melatonin in Normal Sleepers- Normal Sleepers: Melatonin decreased sleep onset latency (SOL) in normal sleepers (weighted mean difference (WMD): -3.9 min; 95- percent CI: -5.3 min., -2.6 min.). The magnitude of this effect appears to be clinically insignificant. There was evidence of possible publication bias in the selection of studies that were analyzed; we found a greater number of studies reporting positive results compared to negative results.

(2) Melatonin increased sleep efficiency in normal sleepers (WMD: 2.3%; 95-percent CI: 0.7%, 3.9%), and this effect was dependent on the timing of sleep, such that the effect of melatonin was greater in daytime sleepers (daytime sleep: WMD: 8.0%; 95- percent CI: 1.0%, 15.0%; night-time sleep: WMD: 1.2%; 95-percent CI: 0%, 2.4%). The magnitude of this effect appears to be clinically insignificant. There was considerable evidence of possible publication bias in the selection of studies analyzed; we found a greater number of studies reporting positive results compared to negative results.

(3) Overall, melatonin did not have an effect on REM latency in normal sleepers, although doses of 1 mg to 3 mg produced a significant increase in REM latency compared to placebo (WMD: 12.7 min.; 95-percent CI: 6.8 min., 18.6 min.), while both higher and lower doses did not show this effect. (Buscemi, et al., 2004)

In regards to the effectiveness of exogenous melatonin in individuals with sleep disorder and specifically those with a primary sleep disorder it is stated as follow:

(1) Melatonin decreased sleep onset latency in people with a primary sleep disorder (WMD: -10.7 min.; 95-percent CI: -17.6 min., -3.7 min.). SOL was decreased greatly in people with delayed sleep phase syndrome (WMD: -38.8 min.; 95-percent CI: -50.3 min., -27.3 min.). The magnitude of this effect appears to be clinically significant. SOL was decreased marginally in patients with insomnia (WMD: -4.3min.; 95-percent CI: - 8.4 min., -0.1 min.). The magnitude of this effect appears to be clinically insignificant. SOL was reduced more in children (less than age 17 years) (WMD: -17.0 min., 95-percent CI: -33.5 min, -0.5 min.) than in adults (age 18-65 years) (WMD: -11.2; 95-percent CI: -27.7 min, 5.4 min.) or elderly patients (greater than age 65 years) (WMD: -7.8 min.; 95-percent CI: -17.4 min., 1.7 min.). The effects of melatonin did not vary with dose or duration of treatment. If the analysis is approached using the Fixed Effects Model, melatonin does not have any effect on sleep onset latency in people with primary insomnia.

(2) Melatonin did not have an effect on sleep efficiency in people with primary sleep disorders; the effects of melatonin did not vary by age, type of primary sleep disorder, dose, or duration of treatment.

(3) Melatonin did not have an effect on sleep quality, wakefulness after sleep onset (WASO), total sleep time, or percent time spent in REM sleep.

(4) Generally, these studies were of moderate-to-high quality. (Buscemi, et al., 2004)

People with a secondary sleep disorder are reported to experience effects including that melatonin "did not have an effect on sleep onset latency in people with a secondary sleep disorder; the effects of melatonin did not differ between children and adults; the effect of melatonin did not vary with dose or duration of treatment." (Buscemi, et al., 2004) IN addition, melatonin increased sleep efficiency in people with a secondary sleep disorder and the effect of melatonin's did not vary by age, dose or duration of treatment. " (Buscemi, et al., 2004)

In those suffering from sleep restriction the study reports that there was not an effect on sleep onset latency in those that suffer from sleep restriction as the effect of melatonin did not experience variation according to dose or sleep restriction disorder type. In addition there was no effect on sleep efficiency by melatonin among those with sleep restriction and no variation of melatonin by dose is noted. The study found that there was no effect on the quality of sleep by melatonin.

The primary mechanism that melatonin uses in the production of sleepiness in humans is not clear however, three primary reasons are cited including:

(1) the mechanism may involve a phase-shift of the endogenous circadian pacemaker,

(2) a reduction in core body temperature and/or

(3) a direct action on somnogenic structures of the brain. (Buscemi, et al., 2004)

Bercemi et al. concludes by stating that there is a need for more in the way of research studies in these areas of inquiry and specifically that there is a need for "the conditions of these studies to be clearly defined, especially with respect to the formulation and pharmacology of the melatonin product used in these studies. For studies involving melatonin administration to normal sleepers, the presence of substantial heterogeneity and evidence of publication bias necessitates more research in this area." (Buscemi, et al., 2004)

Summary and Conclusion

From the literature reviewed in this present study it is indicated that melatonin is not effective in the treatment of most sleep disorders with only short-term use. Additionally there is evidence which indicates a link between endogenous melatonin and the sleeping cycle as well as evidence indicated a link between endogenous and melatonin and the temperature rhythm