Assignment #3: Pathology

Effects of Melatonin:

Melatonin's actions include brain, pituitary, and antigonadal; many of these effects were discussed in Assignment #1 and a breif overview follows. Refer to Assignment #1 (below) for further details and references.

Melatonin is involved in the regulation of many physiological processes, including:

1. Stimulatory/inhibitory effects on mammalian reproduction

• Melatonin inhibits gonadal maturation by reducing the rate of GnRH (gonadotropin releasing hormone) secretion by the pituitary gland (Martini, 2006).
  It is also known that melatonin can have both inhibitory AND stimulatory effects on the mammalian reproductive system depending on:

• the context in which it is released
• the pattern of release (i.e. breif vs. long pulses)

2. Immune function

• A main target of melatonin is a primary organ of the immune system; the thymus. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides, lymphokines, and perhaps by pituitary hormones (Maestroni, 2007).

3. Metabolism

• Melatonin is an effective antioxidant which protects the central nervous system from damage by free radicals such as nitric oxide and hydrogen peroxide (Martini, 2006).

4. Circadian rhythms

• Our sleep cycle is greatly influenced by the pulsatile secretion of melatonin following a circadian rhythm. Light suppresses the biosynthesis of melatonin during the day or in a well lit room. As night falls, or if we are left in a dark room for some time, the amount of light entering the eye is diminished. Seasonal changes in the daylight period will also have an affect on melatonin secretion, leading to some interesting changes in the animal.

(Hadley & Levine, 2007).


Pathology & Uses

Day-to-day events and their effects on melatonin levels:

• Exposure to excessive light at night, or too little light during the day can disrupt the body’s normal melatonin cycles, and therefore lead to loss of synchony. This can lead to drowsiness and insomia:
  
• "Jet lag" is the term given to the effect of disrupted sleep patterns during traveling. Traveling across time zones may force one to sleep during times in which they are used to being awake, or vice versa. This can produce stressful physical and psychological symptoms. The body must adjust to the new light-dark periods by shifting the production of melatonin.
• Shift work also causes disruptions in the normal circadian rhythm with alternating day and night shifts, and therefore, alternative sleeping patterns. The pineal will continue to produce melatonin at night, despite the need to stay awake during an evening shift, causing drowsiness and fatigue.
• Poor vision or blindness can also disrupt melatonin cycles as the supraochiasmatic nucleus cannot properly respond to light cues.
  
• Melatonin secretion declines with age; hence children sleep more than elderly.
  

Therapeutic use: Melatonin supplements as a treatment for various disorders

1. Insomnia - a sleep disorder
A few studies suggest administering melatonin supplements may be modestly effective at inducing sleep:

• in people with already disrupted circadian rhythms (see examples above)
• in people with low melatonin levels (eg. elderly, schizophrenic patients)
• and prevent jet lag during traveling

Although results are still controversial, and there is the suggestion of a placebo effect. However, patients taking melatonin supplements found:

• decreased time in falling asleep
• increased number of hours of sleep
• increased alertness throughout the day
  

More studies need to be done to further explore these results and to examine long-term effects of supplemental melatonin.

2. Osteoporosis

Melatonin has demonstrated the ability to stimulate osteoblasts, therefore promoting bone growth. Osteoporosis is more common in the elderly, especially post-menopausal women. This correlates with the decreasing levels of melatonin with age. Current studies are investigating the use of melatonin as a preventative measure for osteoporosis.

3.Depression

Studies have shown that people with manic depression or panic disorders have low levels of melatonin. Also, melatonin has been found to alleviate both depression and anxiety in postmenopausal women.
Low melatonin levels are also found in individuals with Seasonal Affective Disorder (SAD) is temporary, mild depression that correlates with the changing seasons. During the winter months, when days are shorter and light exposure is minimal, some people tend to become lethargic, moody, and depressed due to over-production of melatonin. This is more common at high latitudes, where days are shorter and sunlight is lacking (Martini, 2006).
Administration of melatonin has seen shown to cause an increase in serotonin, which in turn helps alleviate symptoms of both major and mild depression. It is important to note that poorly-timed melatonin administration may worsen depression by affecting normal circadian rhythms.

4. Breast & Prostate Cancer

Several studies indicate that low melatonin levels may be linked with increased risk of breast and prostate cancer. Melatonin is an immune system stimulant, and has been shown to actually blocks the growth of certain cancerous cells in test tube studies as well as the shrinking of tumours. There is some evidence that supports administration of melatonin to enhance the effects of some chemotherapy drugs which typically cause thrombocytopenia (i.e. decreased blood platelet count) which leads to decreased clotting. Melatonin helps to maintain platelet count in the blood and prevent excessive bleeds.

5. Rheumatoid Arthritis

Rheumatoid arthritus is a chronic autoimmune condition in which the immune system attacks the joints, leading to inflammation and destruction. Melatonin levels are found to be lower in patients with rheumatoid arthritis than in healthy individuals without arthritis. The anti-inflammatory medication indomethacin has a chemical structure very similar to melatonin. Based on theory (there have been no studies done yet), melatonin supplements may work in a similar fashion.

Administration & Dosage:
Melatonin is available in several pharmaceutical forms:

• tablets
• capsules
• cream
• lozenges

There is currently no recommended dose for melatonin supplements. Lower appear to work well, with higher doses being 'overkill'; causing anxiety and irritability instead of inducing sleep, etc. Our body normally produces less than 0.3 mg/day, so daily doses of this size may be beneficial.
There is also some concern that taking excessive melatonin may "numb" the SCN, or may have unknown effects on the reproductive system (Hadley & Levine, 2007).

References:

Hadley, Mac E, and Jon E. Levine. Endocrinology. 6th ed. Upper Saddle River, NJ: Pearson Prentice Hall, 2007.

Maestroni, Georges J. M. "The immunoneuroendocrine role of melatonin." Journal of Pineal Research 14(2007): 1-10.

Martini, Frederic H. Fundamentals of Anatomy and Physiology. 7th ed. San Francisco, CA: Pearson Benjamin Cummings, 2006.

University of Maryland Medical Center "Melatonin." 4 Nov 2008 .