MELATONIN KEEPS THE TIMING RIGHT

by Abraham Kryger, MD, DMD.

Melatonin is the hormone of the night. New 21^st century diseases such as jet lag or shift work have created a new field of medicine called chronobiology . The science of the timing of life cycles has created a new group of pharmaceuticals known as “chronobiotics” among which melatonin is the prototype. Melatonin is a natural brain hormone regulated by light. These chronobiotic compounds have the ability to regulate various bodily functions using hormones and restore the balance when diseases of cycle regulation occur.

Cycles are a constant on the Earth. Day to night and spring to summer are examples of environmental cycles. Waking and sleeping, sexual drive and reproduction are human cycles. Humans are forced to follow environmental cycles. regardless of an individuals location on the planet , This human circadian (day-night cycle) pacemaker or biologic clock maintains the capacity to cycle so accurately that it can detect seasonal changes in day length.

Human systems cycle every 24 hours. Humans maintain this cycle even if they travel deep down into the earth or up into space where light and darkness do not vary on a 24 hour basis. After a period of about three months in space however, the cycle becomes scattered and stops functioning. The treatment for circadian rhythm disorders caused by internal factors such as sleep disorder or blindness and aging is now available over the counter.

Hormones regulate the cycles of men and women. Human sexual function is dependent on this self regulating inter-relationship between hormones. The darkness of night provides the trigger for most of our sexual urges.. This so called hormone cascade is the basis of the sexual drive and erectile function in men and orgasm in women. Brain chemicals released during the night affect human functioning during the day.

Melatonin is essential for normal sleep and awake cycling, chiefly in the elderly. Melatonin secreted by the pineal gland regulates oxytocin originating from the pituitary gland which consequently regulates testosterone secretion from the testicles. Brain hormones regulate other hormones with feedback loops and self adjusting systems as a backup. As you read more you will understand the complex juggling act taking place in our sex glands and other hormone secreting organs. .

Circadian rhythm problems are becoming more common in civilized countries. The existence of a biologic clock affecting human behavior in response to environmental clues like light/dark cycles has been scientifically proven. This property called “chronobiosis” is present in every living animal species. Even insects have a sleep and awake cycle. Therefore flies when they sit on the ceiling are often asleep which is why you can sneak up on them.

In the human body melatonin provides the ticking of our biologic clock. Melatonin is a hormone secreted primarily at night, reaching levels 10 times higher than those present in the daytime. This clock regulates our hormone release. Have you been told by your doctor that you need to exercise to get more energy ? If you realize that light and energy are equivalent you might understand what this means.

The body charges its energy battery during sleep! During exercise or any activity the body burns up energy known as calories. Then at night when melatonin levels are peaking, the body creates energy for the next day. The creation of energy involves a complex biochemical process. Inadequate sleep produces inadequate energy Cycles of sleep and wakefulness are the most obvious circadian rhythms seen in animals. We burn calories during the day and store them during the night. This is another good reason not to eat before going to bed.

During sleep different parts of the brain communicate. An area of the brain called the hypothalamus, located directly above the crossing of the optic nerves from our eyes, synchronizes the periodic responses from day to night or from season to season. This clock acts like a pacemaker regulating various cycles in all mammals and several other species which sleep during the night.

Animals which sleep during the day also store energy available for their night time escapades. This circadian clock mechanism is called the hypothalamic suprachiasmatic nucleus or ( SCN). Without a functional circadian clock one cannot tell the difference between day and night. Many elderly people find that they wake up at night and sleep during the day. Some people from night shift workers to street walkers find they wake up during the night ready to go as a result of a dysfunctional circadian clock. Most people live with this condition untreated for years and suffer in many ways.

The Pineal Gland -The Third Eye!

Melatonin is secreted by the pineal gland during the night. The pineal gland is the mystical third eye located deep inside the brain. The amazing ability of the pineal to actually sense light depends on a complicated pathway from the eyes. In normal volunteers, monitored by clinical laboratory testing, hormone measurements were made for 24 hours following the administration of oral melatonin. The release of several hormones was stimulated by melatonin indicating that it plays a vital role in the regulation of the circadian sleep-wake cycle and hormone regulation. Without adequate melatonin for sleep someone would feel like a walking zombie.

If you think of the brain as closed fist, then the second and third fingers would be pointing at the hypothalamus and pituitary glands. The pineal gland sits even deeper within the brain directly above these glands. The suprachiasmatic nuclei, abbreviated SCN, contains the circadian pacemaker which sets the biologic clock. Each night the SCN sends impulses, via a series of nerve fibers in the hypothalamus, up to the pineal gland to stimulate melatonin secretion, which in turn, induces sleep. At the same time two other hormones: vasopressin and oxytocin are triggered to be released from the back portion of the pituitary gland. Vasopressin prevents nighttime urination and responds to the degree of hydration in the brain. If one drinks too much liquid during the evening hours, sleep becomes interrupted as levels of vasopressin decrease.

Hormones spikes and drops are all coordinated perfectly by the biologic clock in the SCN. The timing mechanism in the SCN itself is controlled by sunlight that enters the eyes, strikes the retina and ultimately reaches the SCN via the retinohypothalamic pathway or the RHT. The SCN operates through the RHT under the influence of light. Regulating hormones are produced in the pituitary gland which stimulate the end organs to produce hormones. Hormone cycles are much like a roller coaster. When these cycles fall out of balance everybody feel like they have PMS. (1,2).

Melatonin as Regulator of Biologic ( Circadian) Rhythms

Dear Dr. K, I have been caring for a son who has been diagnosed with bipolar w/schizophrenic tendencies. There was a legal issue that dragged throughout the whole last year. His illness is so up and down and unpredictable. He is dealing with it accordingly now and they are trying different meds to help him. I have been his sole support system (at home) he has a therapist and psychiatrist, but I have been the one that everybody has depended on to aid him. I will do it until the day I die. That is not the problem. (or maybe it is) Lately, I cannot function like I normally do. I normally, keep a spotless house, have dinner on the table, am busy with lots of activities and friends. Today, I look for any excuse NOT to be with my friends, I leave laundry in the dryer for days, I don't clean, I don't eat right, I can't sleep and I'm extremely edgy and moody to people. I know what depression can be, I have learned about mental illness to a great degree, although I never felt it could hit me, I was the strongest, I was always up. I was always the life of the party. I can't tell you the last time I have really enjoyed myself. I'm worried now because it's not like I can do anything about this, it's really weird, I can try to even make myself a "list of things to do" around the house and even though I know they need to be done, and it is my nature to do these things without prompt, I just don't do them. I don't know how to explain that. I just don't do any of it. I don't see sunshine anymore. I used to love the sun, I just can't seem to find it even when it's shinning above me. Lisa, BC, Canada.

The sun provides our solar light cycle of day and night and drives circadian cycles—a process called “entrainment”. Sunshine regulates the rhythms of rest and activity, as well as the rhythms of a large number of physiologic and hormonal functions mentioned earlier. Essentially, the melatonin rhythm appears to be a type of hormonal code established early in the evolutionary process.

Over time, the environmental light-dark cycle transmitting information is used by an organism for both circadian and seasonal time organization. Cycles are programmed into our brains. The melatonin rhythm creates a hormonal signal for the circadian clock. It is much like the software of a computer. The periodic secretion of melatonin in response to the absence of light, acting as a watch for any system that can ‘read’ the message. The rhythmic nocturnal secretion is dependent on the SCN but the duration of the nocturnal melatonin production is directly related to the length of the dark period. If someone does not sleep in a normal pattern they cannot generate enough melatonin during the night.

Melatonin has practical uses in animals as well as humans. It is through changes in the duration of melatonin release, that the brain integrates the light cycle information, much like the on and off switch providing the computer language for programming. Science has harnessed this finding by the systematic use of melatonin on farms to control seasonal functions (e.g. fur growth, reproduction, milk production, etc.). Melatonin can be very useful in this respect as it can provide the signal under human control for increasing the length of a season artificially.

The molecule of melatonin has persisted throughout evolution. Its presence has been demonstrated in almost all types of organisms from plants and simple single celled organisms called protozoa to people. During evolution, melatonin is believed to have mediated dark adaptation. This gave man and other animals the ability to see in dim light and perceive movement even though vision was not clear. Dark adaptation allows humans and other animals to sleep safely and rest during the night avoiding danger. A restful night of sleep permitted the storing and converting of energy which was used during the day.

The effectiveness of melatonin as a drug is limited. Melatonin appears to be secreted into the blood in short bursts superimposed on a maintained “baseline concentration. The half-life of a hormone is the length of time required for the blood level to reach 50% of its therapeutic or effective level. The half life of melatonin appears to be less than 30 minutes. This means that half of the serum melatonin level is used up in only one half of an hour. This provides a very small window for its use therapeutically.

Melatonin is created from simple protein constituents called amino acids. Amino acids are the building blocks of protein molecules. Tryptophan, an amino acid derived from protein sources, undergoes a series of enzymatic reactions to produce melatonin. The rhythm in melatonin secretion is generated internally by the circadian pacemaker, in the SCN, and is regulated by environmental light/:dark cycle.

In mammals two types of melatonin receptors have already been determined and cloned (Mela and Melb). Soon others will soon be characterized and the list of melatonin receptor-containing organs will grow. Most of our normal functioning systems (e.g. immune system, sexuality and the cardiovascular and digestive systems) display time related organization.

In spine bearing animals called vertebrates, the pineal gland is the single largest source of melatonin production although in non-mammalian vertebrates, other organs (e.g. retina, harderian gland and GI tract.) may contribute significantly to the blood melatonin levels. The universal presence of melatonin relates to its lipophilic or fat-loving nature, enabling it to cross all biological barriers which are lipid membranes and to diffuse into every cellular compartment.

In spineless invertebrates, on the other hand, the pineal gland is absent and, therefore, melatonin secretion is clearly derived from other sources Regardless of the site of synthesis and the nature of the organism, melatonin is secreted in the night and the melatonin biosynthetic pathway remains essentially the same. (5).

Melatonin through its action on this biologic clock, synchronizes disrupted circadian rhythms, and regulates a variety of daily and seasonal changes affecting both the physiology and behavior of animals. Disorders are known to result from a disturbance of such organization (e.g. during aging, surgery, illness, andropause and menopause). The potential therapeutic use of melatonin is great; but it should not be sold over the counter. Melatonin should be used only under medical supervision. Trying to adjust your own melatonin level is much like performing your own brain surgery. (6)

How Does Melatonin Work ?

Hormone deficiency can spring from human conflicts with the environment. Hormones are responsible for the amazing changes which occur in our bodies. Even our brains are affected by hormones as we shift from one day to the next. At midnight, with the absence of light, certain hormonal triggers are set in motion which affect us during the night and into the following day. At midnight, the pineal gland, protected as it sits in the middle of the skull, secretes increased melatonin. This event is totally regulated by the absence of light. The pineal gland is the mystical “third eye”, recently discovered to have the ability to sense the presence of light even in blind people.

The hormones of both blind and seeing people are controlled by this response to light. Clinically depressed patients have a totally opposite or abnormal pattern of hormone cycles. Their melatonin levels are out of phase. Many depressed patients are sleepy during the day and awake during the night. Others cannot wake up till late morning and then are sleepy by dinnertime. A few depressed people cannot even get out of bed, they feel so terrible in the mornings when the light shines into their eyes, thinking “Oh no, not another day! I didn’t sleep enough last night”. The cycle of life includes melatonin.

Melatonin has been found to regulate both daytime and nighttime cycles as well as seasonal mating behaviors. The release of melatonin in response to light is fascinating. Solar energy drives plants to become food for humans and animals who then metabolize and exhale carbon dioxide. This follows a sequence of events which binds all living things on the planet to the action of sunshine. Sunshine is used by the plants to produce oxygen which is then inhaled by animals who produce carbon dioxide. In this cyclical complex process several beneficial effects occur which have profound effects on normal human functioning.

Organisms make melatonin from simple amino acids. Melatonin (N-acetyl-5-methoxytryptamine) is an evolutionary, highly conserved molecule that is formed from tryptophan, a simple amino acid. Amino acids were the building blocks of life. Tryptophan, an amino acid also generates serotonin, a neurotransmitter which is deficient in most types of depression. Serotonin is also affected by the female menstrual cycle. Although the hormone is synthesized mainly by the pineal gland, to a lesser extent it is made by other tissues—such as the eye and the gastrointestinal tract.

The melatonin-generating system is characterized by three basic features:

photosensitivity or response to different levels of light

(2) diurnal (or circadian) rhythmicity with highest levels of the hormone production occurring at night during darkness

(3) age-related decrease in its activity.

Melatonin is very safe and plays an important role in regulating the clock and calendar information of all living organisms, including man. While it is secreted by the pineal gland, it exhibits both a sleep-wake rhythm and a seasonal rhythm in humans. Melatonin has a mild sedative effect and has been used effectively in synchronizing the sleep-wake cycle of patients with sleep disorders. Melatonin causes a direct sedative-hypnotic action, with no serious toxic or side effects even after consumption of large doses. Not too many drugs can make that claim.

Melatonin has a physiologic role as a sleep inducer in man. It also has certain effects on the human circadian rhythms (day-night cycle) , the reproductive cycle and the hormonal system. Melatonin has been shown to control seasonal mating changes in a wide variety of species as well as the levels of the hormones testosterone, oxytocin, vasopressin, cortisol and growth hormone. Many drugs and pathological conditions change melatonin levels in the circulation. This information is not provided on the melatonin labels.

Melatonin levels drop with age. The temporary elevated nocturnal melatonin secretion during menopause may be related to the existence of a low estrogen/testosterone environment. The age-related decrease in melatonin secretion observed in other conditions is most likely attributable to other age-related factors and may be due to the changing daily patterns of oxytocin, vasopressin and growth hormone release with aging.(23,24)

The Pituitary Gland, Source of Hormone Regulation

The pituitary has two distinct parts , each of which secrete totally different hormones. Most of the regulatory hormones, GH, FSH, LH, ACTH, TSH, Prolactin (PRL) are secreted by the anterior pituitary and only Oxytocin (OT and Vasopressin ( VP) are secreted from the posterior pituitary or “neurohypophysis” There are also hormones secreted from the intermediate lobe from the dorsal raphe which regulate melanin (melanostimulating hormone or MSH) but these will be discussed in another issue.

The posterior part of the pituitary is actually an extension of the thalamus and contains neurosecretory products of the supraoptic and paraventricular nuclei. (PVN) You will recall that these neurons are light sensitive and regulate the release of melatonin determining the circadian rhythm as well. Oxytocin was the first polypeptide hormone to be synthesized almost 40 years ago . It is used as a nasal spray or injection to induce labor. After decades of classic research on its secretion from the neurohypophysis and its potential effects in the uterus and the mammary gland, oxytocin has, in the last 15 years, been proven to be “a centrally distributed neuropeptide with a broad spectrum of behavioral effects with a diurnal pattern of secretion” (1) . The baroreceptor system influences the secretion of both oxytocin and vasopressin, with effects on basal secretion as well as a response to an osmotic stimulus. Oxytocin will be discussed first and then Vasopressin.

Oxytocin is a major sex hormone. By controlling mounting behavior and the sexual drive, oxytocin acts by increasing the metabolism of testosterone. Oxytocin is also involved in sexual response as its secretion can be increased by stimulating the nipples. Once released in spurts in certain situations, oxytocin causes either the prostate or the uterus to contract causing flushing and increased brain blood flow during orgasm. Oxytocin can induce aggressive sexual behavior in mammals of either sex.

Oxytocin increases to maximum signaling the onset of labor at the end of pregnancy. Of particular interest are the reports of potent effects of oxytocin on many reproductive and social behaviors such as maternal behavior, female sexual receptivity (lordosis), penile erection and penile sensitivity, male mounting behavior and side by side contact ( many of the intimate features of the sexual act).

Oxytocin (OT) also has anti-stress and blood-pressure-lowering effects in humankind through its effect on the hypothalamic-pituitary-axis (HPA). OT can affect cortisol production and can produce increased brain blood flow , acting as an “anti-stress hormone”.(2) OT is responsible for ejaculation during the sexual act and the maintenance of prostate health as well by its regulatory effects on the 5 AR enzyme. These newly discovered functions of Oxytocin provide a fascinating glimpse into the sexual act from a higher center of brain activity.

Stress and the Fear Response

Clinical and preclinical evidence links stress to drug dependence. Stress is accompanied by the rapid modification of brain and body physiology which leads to release of neuroactive hormones, including biogenic amines and adrenal steroids, which activate the same brain circuitry, as stimulant drugs, such as cocaine and amphetamines. Some preclinical studies showed that stress and elevated plasma concentrations of glucocorticoids increase acquisition and maintenance of stimulant use in rats, whereas other studies revealed that animals with inherently hypoactive HPA axis are more vulnerable to stimulant “abuse”. In humans cocaine acutely activates the HPA axis, and in chronic cocaine abusers early abstinence is accompanied by alterations of the HPA axis function, with distinct patterns of hormonal changes characteristic for different subgroups of addicts. Some of these changes correspond to psychiatric comorbidities, which may be predictive of propensity to relapse. Hemispheric laterality plays a role in the stress-induced activation of the HPA axis, with right prefrontal cortex (PFC) having mostly stimulatory effects and the left, inhibitory effects. Brain-imaging studies showed preferential alteration of structure and function of the right cerebral hemisphere in cocaine addicts. Activation of the right PFC and inhibition of the left was noted in typical depressive disorders, and right hemispheric hypoactivity was reported in attention deficit hyperactivity and antisocial personality disorders, which are highly comorbid with stimulant dependence. Distinct patterns of hemispheric predominance or hypofunction between individuals may contribute to vulnerability or resilience to stimulant dependence. The nature and significance of the link between stress and activity of HPA axis, and vulnerability to drug dependence is not clear and deserves further study. (27)

The pineal gland secretes melatonin mainly under the influence of the suprachiasmatic nucleus (SCN) neurons which respond to light stimulation. As mentioned , fear or novel stimuli inhibit vasopressin (VP) and facilitate oxytocin (OT) release from the pituitary. The SCN-pineal gland system may modulate all vasopressin and oxytocin responses to conditioned fear stimuli or other stressors.(5)

Fear is an incredibly powerful motivator! The fear response is believed to have profound stress inducing effects in the posterior pituitary by activating oxytocin. In response to various stressors, oxytocin (OT) is released not only into blood, but also into certain brain regions to try and restore homeostasis or balance. These regulating hormones usually increase during the night to restore homeostasis. In some cases dysregulation may result along with chronic stress effects.

Stress can create disease by disrupting the balance. Conditioned fear or novel environmental stimuli ( new job, marriage, childbirth, death and so on ) both suppress vasopressin (VP) and increase oxytocin (OT) release. The purpose of OT is to restore homeostasis by reducing the effects of the “stress”. To accomplish this end OT and VP both regulate adrenal function and release of cortisol. The pineal gland plays a role in response to light activated melatonin release. It is easy to see that the interdependence of hormones is crucial to maintaining balance.

These stressors can become a part of life in the modern world. The constant stress can result in a modulation of OT receptor-binding by both steroids (cortisol) and melatonin in humans. Both of these posterior pituitary hormones affect the physiologic and psychological systems related to reproduction and sexual functioning in humans.

Oxytocin release has profound effects. Its action in the brain stimulates the milk ejection reflex in women and semen ejaculation in men. Similarly, released VP is important in the modulation of a range of behaviors. It is quite possible that the whole range of behaviors comprising ‘social’ (or ‘anti-social’) and ‘maternal’ or ‘paternal’ behavior can be related to the expression of these hormones and their receptors . (6)

Certain behaviors and emotions are hormonally driven. The concept of the chemical regulation of emotions and behaviors is not foreign to human physiology. The wide range of depressive symptoms from lack of pleasure in daily activities to loss of interest in sex is reorganized by neurotransmitters in the brain and spinal cord. We are our emotions and we may be nothing more than hormones firing at random sequence, striking receptors like a pinball machine.

Melatonin and Sleep

Healthy sleep has been proven to be the single most important determinant in predicting longevity. It is more influential than diet, exercise or heredity. Unfortunately our modern culture has created a geometric rise in the occurrence of sleep deprivation. Since modern humans use artificial light to extend their period of wakefulness and activity into the late evening hours, they succumb to a short night sleep cycle. These cycles are not always associated with restful, refreshing sleep. Humans have also increasingly insulated themselves from the natural cycles of light and darkness particularly in the cities. Artificially lighted long days therefore cause modern humans to become systematically sleep deprived. Sleep is sacrificed to meet the demands of their endless days.

Deadly sleep disorders are the result. Sleep problems shorten countless lives despite the availability of simple treatments. Doctors regard sleep deprivation as a fact of life and do little to promote sleep health or awareness. Meanwhile, the physical, emotional and psychological costs of unhealthy sleep continue to mount. Sleep has a powerful effect on the immune system to weight regulation and creates a feeling of well-being. Many people long for a good night’s sleep from which they can awaken refreshed and ready to go.

Most sleep disorders respond to simple melatonin supplementation. Melatonin can act on sleep by delaying the sleep-wake cycle so that sleep onset occurs earlier or later than usual. The timing of use of the melatonin is critical to its proper action. The beneficial effects of melatonin have been observed in various sleep disturbance syndromes from sleep apnea (OSA) to insomnia. Melatonin is also used to treat jet lag and in night shift workers to successfully re-entrain their disrupted circadian rhythms.

The administration of melatonin may be effective for improving sleep even in blind subjects unable to synchronize with the solar light cycle. Melatonin is an effective hypnotic for insomniacs or travelers who suffer from jet lag. Sleep disorders in elderly people respond very well to melatonin supplementation and its safety has been proven over the last four decades. The dose and timing of use are critical. This information is not listed on non FDA regulated labels.

It is important to realize that sensing the light for pineal function is not a part of vision. As a matter of fact, interrupting the retinohypothalamic tract ( RHT) abolishes circadian entrainment, but not vision or the reflex response to light.

The reflex response to light occurs when light is shone into one eye and the pupils in both eyes contract to decrease the amount of light entering the eye. This indicates that both eyes are connected in the brain even though only one eye may be stimulated with light.

Cutting the optic tracts from the eyes to the brain abolishes vision and the light reflex, but not circadian entrainment or the light pathway to the pineal. In the absence of light, people still show a circadian rhythmicity, but the cycle of rest and activity is not exactly 24 hours. The solar cycle is necessary to entrain the brain to an exact 24 hour cycle. This means that the eyes are not only involved in seeing but also in the sensing mechanism for normal circadian functioning.

The biologic clock requires light to operate. People who are completely blind have no way to control their circadian pacemaker or SCN; they can use social cues to modify their sleep-wake behavior, but the period of the pacemaker is not 24 hours. Czeisler et al. at Harvard Medical School reported the results of their study of 11 blind subjects with no conscious perception of light. Three of these patients showed a normal suppression of melatonin secretion by bright light, indicating that although the optic tracts were damaged, the RHT was functioning normally. These subjects showed normal suppression of melatonin secretion by daylight. They were always in synchrony and slept well at night. The other seven blind subjects were not in synchrony. If they tried to sleep when melatonin levels were low, they had serious sleep disturbances. If they tried to sleep when melatonin levels peaked, they slept well and felt well. (3)

Blind subjects who have neither the perception of light nor the hormonal response to light are doubly handicapped. In order to prove how important the light-dark cycle is to the circadian clock and the organization of the sleep-wake cycle, experiments were conducted in blind people. Not only can they not perceive the visual world, but they also cannot synchronize their lives to it. Their eyes may be blind, but their whole bodies are in darkness. Their handicap prevents the function of a highly organized and efficient sleep system.

Melatonin has been patented. In the 1960s, Richard Wurtman, a medical researcher, completed pioneering work on the effects of light and darkness on the pineal secretion of melatonin. He and others traced the neurologic “wiring” of the complex circadian system including the RHT. In 1988, Dr.Wurtman applied for a patent for the use of melatonin to treat sleep disorders, and a small Lexington, Massachusetts company called Interneuron Pharmaceuticals—obtained the rights to the patent application. Twenty four years later, Interneuron still hopes to market melatonin as a prescription hypnotic.

Dr. Wurtman and his investigators concluded that melatonin may be as effective a hypnotic as the common tranquilizers: Valium, Librium, Ativan or Xanax. without any side effects or dependence. The rhythmic nocturnal secretion of Melatonin is dependent on the biologic clock, but the duration of its nighttime production is directly related to the length of the dark/light period. Therefore this hormone can be totally regulated by light.

Melatonin works quickly and effectively in low doses. According to Wurtman, who compared melatonin with placebo, melatonin (at all doses) decreased the time it took to fall asleep, and increased sleep duration. Subjects who received melatonin 1 mg fell asleep in an average of 6 minutes, compared with 17 minutes for subjects who received placebo. Too high doses of melatonin caused daytime sleepiness as well.

.Melatonin is not an FDA approved drug but it is very safe. Currently, melatonin is sold over-the-counter and is quite inexpensive. However, there is no labeling for dosage and side effects. there are no controls for purity. Self-medicating with an unregulated product must be undertaken with care since no warnings are given on the label. Of course most people do not read labels and warnings are ignored more often than they are heeded.

The physiological role of melatonin in humans falls into two categories. The first relates to the self-regulation of circadian rhythm by the suprachiasmatic nucleus-pineal complex.(SCN) or the biologic clock role. The second relates to the promotion of anabolic physiological processes or the anabolic restorative role. This refers to the action of melatonin to regulate certain activities of the body related to the building up of body tissue. In humans, elevated melatonin levels have been associated with reduced core temperature, increased heat loss, reduced alertness, sleepiness, thickening of the skin and enhanced immune responsiveness. Taken together, these changes suggest that melatonin may increase the repair of the body processes promoted during the sleep period.(18, 4).

Exposure to bright light during the early hours of daylight delays the nocturnal melatonin peak. The chronic administration of melatonin was also associated with diminished overall corticosterone secretion and increased sensitivity to glucocorticoid feedback. These findings indicate that chronic melatonin treatment may protect several regulatory components of the HPA axis from glucocorticoid-induced deterioration as occurs in depression.

Melatonin also influences Vasopressin ,the neurohypophysial hormone response in the human to known stimuli of release, such as higher salt concentration , exercise and insulin-induced hypoglycemia. Recent studies have revealed that not only does the release of vasopressin and oxytocin vary over each 24 h, but the respective renal and pregnant uterine responses also show diurnal variations. and alters cortisol, GH, PRL and nocturnal vasopressin secretion, while modification of the sleep pattern decreases vasopressin concentrations and alters its nocturnal peak. (25). This effect manifests as changes in serum and urine osmolality or concentration of bodily fluids. (25) .

Melatonin and Aging

The prolongation of life expectancy and the drastic reduction of fertility rate are the primary cause of an aging world. It is projected that the elderly (above 65) will increase within the next 25 years by 82%, whereas the new born only by 3%. Despite the enormous medical progress during the past few decades, the last years of life are still accompanied by increasing ill health and disability.

The ability to maintain active and independent living for as long as possible is a crucial factor for aging in health and dignity. Therefore, the promotion of healthy aging and the prevention of disability in men, must assume a central role in medical research and medical practice as well as in the formulation of national health and social policies. Effective programs promoting health and aging will ensure a more efficient use of health and social services and improve the quality of life in older persons by enabling them to remain independent and productive.

The most important and drastic gender differences in aging are related to organs and or systems dependent or influenced by reproductive hormones. In distinction to the course of reproductive aging in women, with the rapid decline in sex hormones and expressed by the cessation of menses, aging men experience a slow and continuous decline of hormones.

This decline in endocrine function involves: A decrease of testosterone, Dehydroepiandrosterone (DHEA), estrogens, thyroid stimulating hormone (TSH), growth hormone (GH), insulin-like growth factor-1 (IGF-1), and melatonin. This decrease is concomitant with an increase of LH and FSH. In addition sex hormone binding globulin’s (SHBG) increase with age resulting in further lowering the concentrations of free biologically active androgens. Interventions such as hormone replacement therapy may prevent, delay or alleviate the debilitating conditions which may result from secondary partial endocrine deficiency.

Primary and secondary preventive strategies such as the promotion of a safe environment, healthy lifestyle including proper nutrition, appropriate exercise, avoidance of smoking, avoidance of drug and alcohol abuses, if done effectively, should result in a significant reduction of the health and social costs, reduce pain and suffering, increase the quality of life of the elderly and enable them to remain productive and contribute to the well-being of society. In light of this, public awareness of medical knowledge needs to be increased and basic, clinical, socio-economic and epidemiological research intensified.

Melatonin offers physicians’ the ability to regulate and possibly prevent the most common cancers seen in humans. Melatonin serves as an antioxidant acting as a free radical scavenger and replacement in old age is crucial to permit normal functioning to take place. It is interesting that although Melatonin prevents cancer it is not controlled by prescription. The mechanisms involved in the function of melatonin involve newly discovered receptors which regulate the internal hormonal cascade. This very useful hormone is also effective by skin delivery and may offer a protective effect in men with a family history of cancer of the prostate.

Melatonin levels decrease with age and may result in the common sleep disorders associated with aging. The following facts are accepted:

1. Decline of melatonin production during aging.

2. The role of the pineal gland in the regulation of the ovarian cycle in aged females.

3. The antioxidant effect of melatonin is potent.

The antioxidant effect of melatonin might explain its lifespan-prolonging effect. The age-related decline of pineal melatonin production is not due to the degeneration of the pineal tissue itself. The degenerative changes of the neural structures (serotonergic and noradrenergic neuron systems) innervating the pineal gland and the SCN are responsible for decreased melatonin. The decreased melatonin production of the pineal gland precedes the onset of menopause. The destruction of ovarian cycles can be partly counteracted by melatonin or by 5-hydroxytryptophane administration.

More research is needed on Melatonin’s potential use against multiple human diseases. Melatonin is safe and effective as an antioxidant and sleep restorative in aging humans. Melatonin has powerful anticancer properties yet it is not used in this capacity in Western medicine. Melatonin should be regulated and studied by pharmaceutical companies but as a naturally existing compound it is not patentable and therefore there is no potential for financial gain. It thus becomes the government’s task to protect its citizens and provide guidelines on the use of this powerful hormone.

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