The objective of this article is to review the basis supporting the usefulness of melatonin as an adjuvant therapy for breast cancer BC prevention in several groups of individuals at high risk for this disease. Melatonin, as a result of its antiestrogenic and antioxidant properties, as well as its ability to improve the efficacy and reduce the side effects of conventional antiestrogens, could safely be associated with the antiestrogenic drugs presently in use. In individuals at risk of BC due to night shift work, the light-induced inhibition of melatonin secretion, with the consequent loss of its antiestrogenic effects, would be countered by administering this neurohormone. BC risk from exposure to metalloestrogens, such as cadmium, could be treated with melatonin supplements to individuals at risk of BC due to exposure to this xenoestrogen. The BC risk related to obesity may be reduced by melatonin which decrease body fat mass, inhibits the enhanced aromatase expression in obese women, increases adiponectin secretion, counteracts the oncogenic effects of elevated concentrations of leptin; and decreases blood glucose levels and insulin resistance.
Melatonin and Melatonin breast death: Differential actions on apoptosis in normal and cancer cells. Antitumour activity of melatonin in a mouse model of human prostate cancer: Relationship with hypoxia signalling. Leptin—A growth factor in normal and malignant breast cells and for normal mammary gland development. Tumor regression was achieved in 5 of 12 of the patients Drinking flashing glasses uk no toxicities were noted. The melatonin action on stromal stem cells within pericryptal area in colon cancer model under constant light. Melaotnin cancer: Not your grandmother's cancer. Melatonin could Melatonin breast cervical cancer cell viability in vitroand suppress cervical adenocarcinoma metabolism in vivo. Cell Cycle Res.
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Melatonin might lower blood pressure. The light-dark regimen and cancer development. Melatonin may also be injected into the veins after a heart attack. Prospective studies, assessing the incident risk of breast cancer, have corroborated the role of low melatonin as a risk factor through measurement of urinary levels. The data supporting each of these oncostatic actions of melatonin are summarized in this review. Int J Cancer. J Biol Regul Homeost Agents. Sleeping problems in people with sleep-wake cycle disturbances. Further, there may be an inverse association between melatonin levels and tumor size in women with existing breast tumors. Studies have shown that circadian disruption, specifically night shift work, is correlated with an increased risk of developing breast cancer. However, it can cause some side Melatknin including headache, short-term feelings of depression, Melatonin breast sleepiness, dizziness, stomach cramps, and irritability. Early research shows that taking melatonin might brexst the loss of vision in people with age-related vision loss. How does it work? Some medications used for diabetes include glimepiride Amarylglyburide DiaBeta, Glynase PresTab, Melatonin breastinsulin, pioglitazone Actos Melatonkn, rosiglitazone Avandiachlorpropamide Diabinese Lacy underwear pictures free, glipizide Glucotroltolbutamide Orinaseand Melatonin breast. Some medications used Melatinin prevent seizures include phenobarbital, primidone Mysolinevalproic acid Depakenegabapentin NeurontinZen lesbians Tegretolphenytoin Dilantinand others.
- Some people use melatonin supplements to ease sleep problems or jet lag.
- Scrutinizing the evidence for breast cancer procedures and treatments.
- It is well established that melatonin has oncostatic effects both in vitro and in vivo on various types of cancers, with a unique effect on breast cancer cells.
- Melatonin is a hormone found naturally in the body.
Journal of Cancer. International Journal of Biological Sciences. International Journal of Medical Sciences. Journal of Genomics. Journal of Bone and Joint Infection. Journal of Biomedicine. Global reach, higher impact. Oncomedicine ; Sarah Liu 1 , Chikezie O. Melatonin is a hormone that is secreted by the pineal gland in the brain. Its secretion during periods of darkness represents a hour rhythm controlled by the circadian clock and is pivotal in the regulation of sleep and wake cycles.
Although circadian rhythms are endogenous processes, they can be affected by environmental factors such as light and temperature. In addition to its role in circadian rhythms, melatonin has also been observed to function in the immune system, female menstrual cycles, seasonal behavior, tumor inhibition, and anti-aging processes.
Low levels of normal melatonin have been linked to neoplasia, such as the growth of rat hepatomas and human breast cancer xenografts, circadian phase shifts, sleep disturbances, and immunosuppression.
Since the discovery of melatonin in the early s, significant advancements have provided researchers with the technology to study the hormone in-depth, determine the myriad of processes it acts in, and develop treatment methods for various diseases. By the late s, melatonin's antioxidant property was discovered, and later in the s, studies conducted have affirmed its anticancer effects. The pineal gland hormone, melatonin, is also known as 5-methoxy-N-acetyltryptamine and is synthesized from the amino acid tryptophan and converted into serotonin.
N-acetylserotonin is then finally converted into melatonin by the enzyme hydroxyindole-O-methyltransferase Figure 1. During the night, melatonin production peaks and then falls dramatically during the day with exposure to light.
Although the occurrence of sleep is not necessary for the nocturnal production of melatonin, the presence of darkness is a requirement. As long as an individual is exposed to total darkness, the circadian melatonin signal should remain intact. The effectiveness of melatonin in suppressing various illnesses and cancers has been proven through multiple in vitro and in vivo experiments. Apoptosis is the primary mechanism by which melatonin converts tumor cells to healthy cells.
Melatonin is a hormone secreted by the pineal gland, and its secretion follows a nocturnal circadian rhythm dependent upon the biological clock, an animal's internal hour cycle. The central clock in the body is located in the suprachiasmatic nucleus SCN of the hypothalamus, and it maintains temporal homeostasis by delivering messages throughout the body about the time of day. Levels of melatonin MEL are regulated by various mechanisms including norepinephrine, the clock, and the presence of light.
Production of melatonin is stimulated by the presence of norepinephrine, which is released from sympathetic nerve fibers exclusively at night. The close relationship between the time of day and the production of melatonin suggests its importance in the promotion of sleep. Although sleep is not necessary for the production of melatonin, the presence of darkness is an absolute requirement. Melatonin secretion and release display a circadian rhythm, reaching its highest levels during the night and early morning hours when there is minimal light and its lowest levels during a period of light.
Pineal glands of lower vertebrates are simulated directly by light. Higher level vertebrates, including humans, however, have pineal glands that are not directly photosensitive.
Rather, the gland responds to light via a multisynaptic pathway that includes retinal ganglion cells and the photopigment melanopsin. The retina, which contains three types of photoreceptors rods, cones, and ganglion cells , receives information about light and dark. Several studies have shown that melatonin is produced not only in the pineal gland but also in ocular tissues, specifically the retina, ciliary epithelial cells, and lens cells.
In humans, the action spectra for melatonin suppression has a maximum around nm suggesting that melanopsin, a functional photopigment, plays a role in the photic regulation of melatonin levels, circadian rhythms, and sleep patterns. Given that light affects melatonin secretion and melatonin secretion in turn correlates to sleep, external forms of melatonin has been used to treat insomnia, jet lag, and other sleep disorders.
The various roles of endogenous melatonin secretion in cellular and physiological processes have furthered its use as an exogenous medication for sleep disorders. Studies have shown a correlation between melatonin levels and sleep.
Nocturnal melatonin levels and the quality of sleep tend to decline past puberty. Traveling between different time zones results in an experience commonly known as jet lag, which is characterized by sleep disturbances and fatigue.
These side effects occur due to the inability of the circadian clock to rapidly synchronize to the new environment. As a result, melatonin with its apparent role in clock-setting has been used to combat the effects of jet lag.
When the drug is taken at the destination between 10 pm and midnight, it can correct the side effects of jet lag. A trial conducted on an international cabin crew showed that use of melatonin before arrival had negative effects on recovery while the use of melatonin upon arrival at the destination prompted a significantly faster recovery of energy and alertness. Older people and insomniacs typically display reduced nocturnal melatonin levels and thus are more prone to sleep disturbances.
Melatonin has been used to alleviate the effects of insomnia and reinstate regular nocturnal melatonin levels; however, other studies have shown minimal correlation between the use of melatonin supplements and improved sleep. In several small studies, 5-mg doses of melatonin given at 10 pm resulted in the advancement of sleep by 1.
In contrast, insomniacs who were given melatonin had little change in their sleep. Melatonin has also been found to have positive effects in treating narcolepsy, a chronic sleep disorder characterized by sudden attacks of sleep, overwhelming drowsiness, and rapid-eye-movement sleep deficit. Studies conducted by Buscemi tested the effectiveness of exogenous melatonin in normal sleepers and those with sleep disorders.
It was discovered that in normal sleepers, melatonin had an insignificant effect on REM latency. However, melatonin was found to decrease sleep onset latency significantly in those with primary sleep disorders.
Overall, the studies showed that exogenous melatonin had an effect on SOL in patients with primary sleep disorders but not on sleep efficiency. The findings were reverse in people with secondary sleep disorders. Mounting data shows benefits of using melatonin to promote and improve sleep.
As a result, melatonin supplementation has been used in autistic children who display abnormal melatonin circadian rhythms and low levels of melatonin. In addition to its role in sleep promotion and circadian clocks, melatonin also serves as a protector of macromolecules, nuclear DNA, and mitochondrial DNA by acting as a potent antioxidant and free-radical scavenger.
Melatonin directly scavenges free radicals, stimulates various antioxidant enzymes, inhibits oxidative enzymes, increases the efficiency of mitochondrial oxidative phosphorylation, and thereby reduces electron leakage and the generation of free radicals. Not only does melatonin act as an antioxidant and free-radical scavenger, but it also plays a role in the immune system.
An early indication of the innate immune response is the proliferation of cytokines, including TNF-a, IL-1B, and IL-6 by activated macrophages, all of which are characteristic of the inflammatory response.
Studies have shown that splenocytes from healthy mice treated with high doses of melatonin produced increased levels of IL-1B. Activation of these receptors enhances the release of T-helper cells Type 1 Th1 cytokines, such as gamma-interferon and IL MEL also is involved in the generation of blood cells and platelets in the bone marrow through the stimulation of hemopoietic cytokines or directly affecting progenitor cells such as pre-B cells, monocytes, and natural killer cells.
The hemopoietic effect of MEL in mice and cancer patients are associated with diminished toxicity of chemotherapeutic treatments, thus suggesting a potential addition to the regimen of chemotherapy patients in the effort to reduce the adverse side effects of the treatment. Melatonin has been known to affect the growth of tumors, and its secretion corresponds with the presence of light and a circadian rhythm.
The relationship between melatonin secretion, light, and cancer suggests that an increase in the prevalence of various types of cancer corresponds with industrialization and exposure to more forms of artificial light, thus resulting in lower levels of nocturnal melatonin. In animals, pineal suppression and pinealectomies stimulate the growth and metastasis of experimental cancers of the lung, liver, ovary, pituitary, and prostate.
Clinical evidence and research have also shown the prospective use of melatonin as a treatment for breast cancer patients. It was found that in women with breast cancer, the melatonin levels both in morning and evening were abnormal.
Nocturnal melatonin levels were low while morning urine samples of breast cancer patients displayed high MEL levels, the opposite of what is expected in healthy individuals.
Women with metastatic breast cancer who had not responded to tamoxifen TMX alone were given TMX at noon and melatonin in the evening. Final reports showed a reduction of lesions and a decrease in insulin-like growth factor IGF-1 in patients. After four cycles, the melatonin administered was observed to normalize platelet levels in a majority of the test subjects and cause tumor regression in 5 out of 12 patients with little toxicity reported. Melatonin has also been shown to improve survival rates in patients with prostate and colorectal cancer.
Studies have shown that men with primary localized malignant prostate tumors have extremely low levels of nocturnal melatonin that decrease with an increase in tumor growth. Melatonin injections given in the morning have been found to stimulate cancer growth while injections in the evening contribute to tumor regression. Afternoon injections have no apparent effect.
The relative levels of nocturnal melatonin can be measured by observing the amount of urinary aMT6 excreted. In addition to cancers of the reproductive system, melatonin has also been shown to affect tumor growth in the thyroid, bronchi, and stomach among other forms of cancer. In female patients with thyroid cancer, the levels of aMT6s were extremely low and did not differ from patients with benign thyroid diseases, indicating that thyroid growth negatively affects the proper regulation of the pineal gland.
Results from other melatonin-cancer studies achieved similar results: some studies reported reduced nocturnal aMT6s levels while other studies reported high levels. Results from various studies show that melatonin has an apparent effect on cancer development, but the discrepancies among the studies prompt further research into the relationship between melatonin and cancer. With industrialized society drifting more towards a life situated in the presence of hour light, the occurrence of sleep disorders and abnormal sleep patterns continues to increase.
As a result, circadian rhythms regulating cellular and physiological processes, such as the secretion of melatonin, have taken a significant toll on the ability to synchronize to the environment. Extended periods of exposure to light further inhibit the production and secretion of melatonin from the pineal gland through proteasomal proteolysis.
Decreased endogenous secretion of melatonin has been shown through various clinical and mouse studies and has been linked to a higher risk of certain types of cancer. Recent epidemiological studies have shown that women working night shifts are at a greater risk of breast, endometrial, and colorectal cancer while male night shift workers are at a significantly increased risk of developing prostate cancer presumably due to their increased exposure to light at night.
Data collected from the women involved in epidemiological studies included urinary melatonin levels measuring specifically levels of 6- sulfatoxymelatonin , sleep duration, and shift work. Breast cancer risk was found to be elevated with decreased urinary melatonin levels in the Nurses' Health Study II, but results from the UK Guernsey Cohort study showed very little significant association between levels of urinary melatonin and the risk of breast cancer.
Prolonged exposure to light has been proven to decrease nocturnal melatonin levels and thus promotes an increase in the risk for various types of cancer. Furthermore, melatonin has been shown to inhibit the overproduction of estradiol, which induces cell division of breast cells. A study conducted by Pinheiro on women in the Nurses' Health Study showed a moderate trend in increased breast cancer risk with longer sleep duration.
A study published in the Journal of Pineal Research showed that cancer patients who were unresponsive to conventional therapies were given large doses of melatonin as an alternative treatment. To combat this factor, melatonin inhibits the synthesis of endothelin-1 to block the growth of cancer cells Figure 5 A. MEL has been observed to repress cell proliferation through apoptotic pathways.
Melatonin induces Apaf-1 expression, triggers cytochrome C release, and stimulates caspase-3 and caspase-9 activities and cleavage Figure 5 B , all of which are mechanisms characteristic of apoptosis.
By stimulating natural killer NK cells, monocytes, leukocytes, interleukins, and interferon-gamma as well as activating the cytokine system and cytotoxic activity Figure 6 , melatonin helps maintain immunity to cancer cells.
A Melatonin can suppress growth of tumors by inhibiting transcription of Endothelin-1 EDN1 , an angiogenic factor that promotes the formation of blood vessels around the tumor.
Nevertheless, this small trial demonstrates the possible use of a nontoxic agent to enhance the effectiveness of an otherwise ineffective therapy. However, taking conventional medication seems to be more effective. Not enough is known about the safety of melatonin when used during pregnancy. Taking melatonin along with medications that decrease the immune system might decrease the effectiveness of medications that decrease the immune system. Depression: Melatonin can make symptoms of depression worse. Some people take melatonin by mouth to adjust the body's internal clock.
Melatonin breast. Guest User
Drugs that cause sleepiness and drowsiness are called sedatives. Taking melatonin along with sedative medications might cause too much sleepiness. Some of these sedative medications include clonazepam Klonopin , diazepam Valium , lorazepam Ativan , and others. Medications that cause sleepiness are called sedatives. Some sedative medications include clonazepam Klonopin , lorazepam Ativan , phenobarbital Donnatal , zolpidem Ambien , and others.
The body breaks down melatonin to get rid of it. Verapamil Calan, Covera, Isoptin, Verelan can increase how quickly the body gets rid of melatonin. Taking melatonin along with verapamil Calan, Covera, Isoptin, Verelan might decrease the effectiveness of melatonin. Warfarin Coumadin is used to slow blood clotting. Melatonin might increase the effectiveness of warfarin Coumadin. Taking melatonin along with warfarin Coumadin might increase the chances of bruising and bleeding.
Be sure to have your blood checked regularly. The dose of your warfarin Coumadin might need to be changed. Melatonin might lower blood pressure. Using it along with other herbs and supplements that have this same effect might increase the risk of blood pressure dropping too low in some people. Some of these products include andrographis, casein peptides, cat's claw, coenzyme Q, fish oil, L-arginine, lycium, stinging nettle, theanine, and others. Melatonin might increase the risk for seizures in some people, particularly in children.
Taking supplements that also lower seizure threshold with melatonin might increase the risk even more. Melatonin might increase the effect of herbs that slow blood clotting and might increase the risk of bleeding in some people.
These herbs include angelica, clove, danshen, garlic, ginger, ginkgo, Panax ginseng, red clover, willow, and others. Using melatonin along with herbs that have sedative properties might increase the effects and side effects of melatonin. John's wort, skullcap, valerian, yerba mansa, and others. Taking St. John's wort increases melatonin levels in the body.
In theory, taking St. John's wort with melatonin might increase both the effects and side effects of melatonin. Taking vitex agnus-castus increases melatonin levels in the body. In theory, taking vitex agnus-castus with melatonin might increase both the effects and side effects of melatonin.
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Melatonin may also be injected into the veins after a heart attack. Melatonin may also be injected into the muscle to help treat cancer. Is it effective? Sleep disorders in blind people. Taking melatonin by mouth helps improve sleep disorders in blind children and adults. Trouble falling asleep delayed sleep phase syndrome.
Taking melatonin by mouth appears to reduce the length of time needed to fall asleep in young adults and children who have trouble falling asleep. However, within one year of stopping treatment, this sleeping problem seems to return. Sleeping problems in people with sleep-wake cycle disturbances. Taking melatonin by mouth is helpful for disturbed sleep-wake cycles in children and adolescents with intellectual disabilities, autism, and other central nervous system disorders.
Melatonin also appears to shorten the time it takes for to children with developmental disabilities to fall asleep. In addition, melatonin appears to improve sleep quality in people with reduced rapid-eye movement REM sleep. Also, melatonin appears to reduce the time it takes to fall asleep and the number of sleep interruptions in elderly people with sleep-wake cycle disturbances and dementia.
Possibly Effective for Insomnia caused by beta-blocker drugs. Beta-blocker drugs, such as atenolol and propranolol, are a class of drugs that seem to lower melatonin levels. This might cause problems sleeping. Research shows that taking a melatonin supplement might reduce problems sleeping in patients taking beta-blocker drugs.
Painful uterus disorder called endometriosis. Research shows that taking melatonin daily for 8 weeks reduces pain by It also reduces pain during menstruation, intercourse, and while going to the bathroom. High blood pressure. Taking the controlled-release form of melatonin before bedtime seems to lower blood pressure in people with high blood pressure.
Immediate-release formulations do not seem to work. For primary insomnia insomnia that is not related to a medical or environmental causes , melatonin seems to shorten the amount of time it takes to fall asleep, but only by about 12 minutes. Melatonin does not appear to improve "sleep efficiency," the percentage of time that a person actually spends sleeping during the time set aside for sleeping. Some people say melatonin makes them sleep better, even though tests do not agree.
There is some evidence that melatonin is more likely to help older people than younger people or children. This may be because older people have less melatonin in their bodies to start with. There is some interest in finding out whether melatonin might help with "secondary insomnia. Research to date shows that melatonin might not help to reduce the time it takes to fall asleep in secondary insomnia, but it might improve sleep efficiency.
Jet lag. Most research shows that melatonin can improve certain symptoms of jet lag such as alertness and movement coordination. Melatonin also seems to slightly improve other jet lag symptoms such as daytime sleepiness and tiredness. But, melatonin might not be effective for shortening the time it takes for people with jet lag to fall asleep.
Reducing anxiety before surgery. Melatonin used under the tongue seems to be as effective at reducing anxiety before surgery as midazolam, a conventional medication. It also seems to have fewer side effects in some people. Taking melatonin by mouth also seems to reduce anxiety before surgery, although some conflicting evidence exists. Taking high doses of melatonin with chemotherapy or other cancer treatments might reduce tumor size and improve survival rates in people with tumors.
Applying melatonin gel to the skin before sun exposure seems to prevent sunburn. Applying melatonin cream to the skin before sun exposure seems to help people that are very sensitive to sunlight. But melatonin cream might not prevent sunburn in people with less sensitive skin. Jaw pain temporomandibular disorder. Low blood platelets thrombocytopenia. Taking melatonin by mouth can improve low blood platelet counts associated with cancer, cancer treatment, and other disorders.
Possibly Ineffective for Weight loss from cancer cachexia. Research shows that taking melatonin each evening for 28 days does not improve appetite, body weight, or body composition in people with wasting syndrome from cancer. Memory loss dementia. Most research shows that taking melatonin does not improve behavior or affect symptoms in people with Alzheimer's disease or other forms of memory loss.
But taking melatonin might reduce confusion and restlessness when the sun goes down in people with these conditions. Dry mouth. Taking melatonin by mouth and using melatonin as a mouth rinse doesn't prevent dry mouth in people with head and neck cancer being treated with cancer drugs and radiation.
Exercise performance. Taking melatonin one hour before resistance exercise does not seem to improve performance. Taking melatonin does not appear to improve fertility or pregnancy rates in women undergoing fertility treatments. Adjusting sleep schedule in people who do shift work. Taking melatonin by mouth does not seem to improve sleeping problems in people who do shift work. Likely Ineffective for Withdrawal from drugs called benzodiazepines. Some people take benzodiazepines for sleep problems.
Long-term use can lead to dependence. Taking melatonin at bedtime doesn't help people stop taking these drugs. Although melatonin might improve sleeping problems in people with depression, it does not seem to improve depression itself. There is also some concern that melatonin might worsen symptoms in some people. It is not clear if taking melatonin can prevent depression. Insufficient Evidence to Rate Effectiveness for Age-related vision loss age-related macular degeneration.
Early research shows that taking melatonin might delay the loss of vision in people with age-related vision loss. Early research shows that melatonin can reduce the symptoms of eczema in children years of age. Melatonin can also shorten the time it takes for these children to fall asleep. Attention deficit-hyperactivity disorder ADHD. Limited research shows that melatonin might reduce insomnia in children with ADHD who are taking stimulants. However, improved sleep does not seem to decrease symptoms of ADHD.
Enlarged prostate benign prostatic hyperplasia. Some research shows that taking melatonin can reduce excessive urination at night in some men with enlarged prostate. Bipolar disorder. Early research shows that taking melatonin at bedtime increases sleep duration and reduces manic symptoms in people with bipolar disorder who also have insomnia.
But there are also concerns that taking melatonin might make symptoms worse in some people with bipolar disorder. Taking melatonin by mouth before cataract surgery seems to reduces the pain during surgery.
It might also reduce pressure in the eye before and during cataract surgery. Chronic fatigue syndrome CFS. Some early research shows that taking melatonin in the evening might improve some symptoms of CFS, including fatigue, concentration, and motivation. However, other early research shows that taking melatonin by mouth does not improve CFS symptoms. Lung disease chronic obstructive pulmonary disease. Some evidence shows that taking melatonin improves shortness of breath in people with COPD.
However, it does not seem to improve lung function or exercise capacity. Cluster headache. Taking melatonin 10 mg by mouth every evening might reduce the frequency of cluster headaches.
However, lower doses don't seem to work. Mental function. Early research shows that a single dose of melatonin taken by mouth does not improve thinking skills in healthy adults. Other early research shows that applying a cream containing melatonin to the skin for 2 days does not change mental function in healthy adults. Problems with mental function. Taking a mixture of docosahexaenoic acid DHA , eicosapentaenoic acid EPA , vitamin E, soy, phospholipids, melatonin, and tryptophan appears to slightly improve mental function and sensitively to smell in older people with some problems with mental function.
Evidence shows that taking melatonin nightly for 14 days reduces the risk of delirium in older people. Indigestion dyspepsia. Taking melatonin nightly seems to reduce indigestion. Nighttime bedwetting enuresis. Early research shows that taking melatonin before bed does not reduce the number of wet beds in children with nighttime bedwetting. Melatonin might decrease the severity of pain and stiffness in people with fibromyalgia. Acid reflux disease. Taking melatonin daily at bedtime might improve symptoms of acid reflux, including heartburn.
However, taking conventional medication seems to be more effective. Stomach ulcers caused by H. Evidence shows that taking melatonin together with the drug omeprazole improves healing in people with ulcers caused by H. Irritable bowel syndrome IBS. Early research shows that taking melatonin might improve some, but not all, symptoms of IBS.
Some research shows that melatonin works better in people with IBS in which constipation rather than diarrhea is the main symptom. Menopausal symptoms. Limited research shows that melatonin does not relieve menopausal symptoms.
However, taking melatonin in combination with soy isoflavones might help psychological symptoms associated with menopause. Metabolic syndrome. Early research shows that taking melatonin reduces blood pressure as well as low-density lipoprotein LDL or "bad" cholesterol in people with metabolic syndrome.
Migraine headache. There is some evidence that taking melatonin before bed can prevent episodic migraine headache in adults and children. When headaches do occur, they are milder and pass more quickly. However, other evidence shows that taking melatonin does not reduce the frequency of migraine attacks.
Heart attack. Early research shows that melatonin injected directly into the vein within 2. Withdrawal from nicotine. Taking melatonin 3. Liver disease nonalcoholic steatohepatitis. Some evidence shows that taking melatonin improves markers of liver function in the blood of people with nonalcoholic steatohepatitis. Nonetheless, these studies lend further support to the associated increased risk of work involving circadian disruption.
In a prospective study of 12, women in Finland, developed breast cancer during the study period. A review of studies looking at melatonin metabolites and the duration of sleep supports this. One explanation for these conflicting results is that unlike night-shift work, which has been shown to result in reduced melatonin production, a decrease in sleep duration may not necessarily correlate with melatonin levels.
Melatonin Metabolites and the Associated Risk of Developing Breast Cancer Melatonin can be directly measured in the plasma, although this approach has fallen out of favor because it is unnecessarily invasive and requires sleeping in an observational facility. More recently, urinary metabolites, such as 6-sulphatoxymelatonin aMT6s , have been used as a surrogate marker of melatonin.
Urinary aMT6s correlates well with melatonin levels in blood and saliva and has become the predominant means of measuring melatonin. The Guernsey III recruited 5, women between and A hour urinary sample was obtained at the time of recruitment. In , using public records and pathology reports, cases of breast cancer were found and case controls matched for age, menopausal status, day of menstrual cycle or number of years postmenopausal, and recruitment date.
There were no statistically significant differences in the hour urinary levels of aMT6 in those with breast cancer compared to the case-matched controls, regardless of premenopausal or postmenopausal status OR 0. The results of these studies, outlined below, support the inverse association between nocturnal melatonin levels and the risk of developing breast cancer. Of these, 29, participants agreed to participate in a sub-study between the years — that included a first-morning urine sample and two blood samples age of nurses at the time of these samples was 32— A prospective, case-control study of incident breast cancer cases were evaluated between the time of urine collection and May Urinary metabolite aMT6s levels were divided into quartiles using the matched controls.
No association between receptor status and aMT6 was found in this larger, prospective cohort study. Blood and hour 7 p. Of the 3, participants who were postmenopausal, there were incident breast cancers occurring between the time of enrollment and December 31, , according to the local cancer registry.
These cases were matched to controls. The concentration of aMT6s from postmenopausal women who developed breast cancer between the time of the sample collection and May 31, , was compared to matched controls. Again, an increased amount of aMT6s was statistically associated with a lower risk of breast cancer.
The odds ratio for the highest versus the lowest quartile was 0. Night-Shift Work and Increased Risk of Breast Cancer In , Bartsch and colleagues published the first study demonstrating that melatonin levels are diminished in patients with breast cancer.
In this case-controlled study of 17 primary breast cancer patients awaiting surgery, urinary aMT6s was measured from 10 p. Further, the researchers confirmed their earlier finding that there was a significant and inverse correlation of aMT6s with increasing tumor size in patients with breast cancer. Clinically, this association may serve to support the application of oral melatonin in patients with existing breast cancer, particularly those with concomitant sleep difficulties.
Oral Supplementation of Melatonin Much of the evidence supporting the use of melatonin in treating various cancers comes from clinical trials done by Paolo Lissoni of Italy. He has demonstrated a wide array of beneficial effects of high dose melatonin 10—40 mg daily before bed in patients with advanced cancers of varying origin.
In a pilot study by Lissoni in , melatonin showed benefit in women who had not responded to tamoxifen TMS therapy alone. Two of these 4 responders had singular lung lesions, one had pleural metastasis, and the fourth had skin metastasis.
Of note, circulating levels of insulin-like growth factor IGF-1 decreased in all patients on melatonin, with a significantly greater decrease in those who had a clinical response. Further, 6 of the patients enrolled, and 2 of the 4 responders were estrogen receptor—negative, yet had previously been given tamoxifen due to ineligibility for poly-chemotherapy approaches.
This study was done prior to the advent of aromatase inhibitors, which would certainly be applied today to postmenopausal patients who have progressive disease on tamoxifen. Nevertheless, this small trial demonstrates the possible use of a nontoxic agent to enhance the effectiveness of an otherwise ineffective therapy.
Fourteen women with thrombocytopenia were enrolled and given 20 mg per evening of melatonin for 7 days before beginning weekly epirubicin treatments. After 4 cycles, the induction phase of melatonin normalized platelets in 9 of 12 evaluable patients. There was no further platelet decline in these patients throughout the chemotherapy treatment.
Tumor regression was achieved in 5 of 12 of the patients and no toxicities were noted. This small trial suggests that melatonin may enhance platelet production and decrease thrombocytopenia in breast cancer patients receiving epirubicin. Larger trials confirming this benefit to platelet-depleting drugs, including epirubicin, are needed in order to make such a conclusion.
Prospective studies, assessing the incident risk of breast cancer, have corroborated the role of low melatonin as a risk factor through measurement of urinary levels. Further, there may be an inverse association between melatonin levels and tumor size in women with existing breast tumors. While definitive clinical trials on the effects of supplemental melatonin in breast cancer patients are yet to be done, it has been well demonstrated to be nontoxic at pharmacological doses; this low toxicity profile coupled with the benefits demonstrated in patients with various cancers including breast, make it a candidate for consideration in breast cancer patients, particularly those with late-stage disease.
For more research involving integrative oncology, click here. She received her naturopathic doctorate from National University of Natural Medicine, and completed her residency in naturopathic oncology at Cancer Treatment Centers of America, Tulsa, Oklahoma. She is the past president and treasurer of the Oncology Association of Naturopathic Physicians and secretary of the American Board of Naturopathic Oncology. She has been published in several peer-reviewed journals. Kaczor is based in Portland, Oregon.
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The Role of Melatonin in Cancer Development
The objective of this article is to review the basis supporting the usefulness of melatonin as an adjuvant therapy for breast cancer BC prevention in several groups of individuals at high risk for this disease.
Melatonin, as a result of its antiestrogenic and antioxidant properties, as well as its ability to improve the efficacy and reduce the side effects of conventional antiestrogens, could safely be associated with the antiestrogenic drugs presently in use. In individuals at risk of BC due to night shift work, the light-induced inhibition of melatonin secretion, with the consequent loss of its antiestrogenic effects, would be countered by administering this neurohormone.
BC risk from exposure to metalloestrogens, such as cadmium, could be treated with melatonin supplements to individuals at risk of BC due to exposure to this xenoestrogen. The BC risk related to obesity may be reduced by melatonin which decrease body fat mass, inhibits the enhanced aromatase expression in obese women, increases adiponectin secretion, counteracts the oncogenic effects of elevated concentrations of leptin; and decreases blood glucose levels and insulin resistance.
Breast cancer is one of the most common neoplasias in women, with about 1. In men, the number of new cases expected to be diagnosed in the USA during is approximately [ 2 ].
As a result of significant advances in its diagnosis and treatment, the mortality rate for BC is lower than that of its incidence [ 1 ]. An increased understanding of the etiology and pathogenesis of BC has allowed the definition of populations who are at high risk for developing this kind of tumor. As a consequence of the definition of BC risk factors, the search for preventive therapies for this pathology is an expanding field in medical research.
Obviously, the periodic monitoring of at risk patients is part of the prevention strategies [ 5 ]. Melatonin is an indoleamine secreted mainly by the pineal gland with circadian rhythmicity.
This molecule exerts regulatory actions on multiple physiological functions. From numerous experimental studies carried out in rodents it has been demonstrated that melatonin prevents the promotion and growth of both spontaneous and chemically induced mammary tumors [ 10 , 11 , 12 , 13 , 14 , 15 ]. Furthermore, in vitro, melatonin, at physiological concentrations, inhibits cell proliferation and invasiveness in human breast cancer cells [ 14 , 16 ].
However, despite mounting evidence supporting melatonin actions that relate to BC treatment [ 17 , 18 ], its clinical use in BC therapy, either as the main drug or as an adjuvant therapy in conjunction with other drugs, has only been assayed on a few occasions and these have been mainly related not to the suppression of tumor growth but rather with the relief of symptoms associated with the tumoral process, such as improvement of sleep and life quality [ 19 ], treatment of depressive symptoms and anxiety [ 20 ], p revention of breast radiation dermatitis [ 21 ] or to decrease the toxicity and to increase the efficacy of chemotherapy [ 22 ].
Another reason might be that what oncologists are actually looking for are drugs which act on molecular targets with high specificity, whereas the antitumoral effects of melatonin are mainly based on its ability to modulate general functions i.
Currently, ten clinical trials examining the therapeutic value of melatonin in BC are listed in the ClinicalTrials. Five of them are focused on the relief of symptoms associated with the tumoral process. The remaining five studies examine the therapeutic effects of melatonin either alone two trials or as an adjuvant therapy associated to metformin, vitamin D, fluorouracil, doxorubicin or toremifene three trials in women already diagnosed with BC, with the results still being analyzed.
The aim of this article is to review the evidence that supports the usefulness of melatonin, not for BC treatment, but rather as an adjuvant preventive therapy for BC in several groups of individuals at high risk for this disease.
In this review we will attempt to demonstrate that there is ample evidence which suggests that melatonin could be an efficient complement in at least the following situations: 1 where the reduction of BC risk is based on treatment with antiestrogenic drugs; 2 when the risk of BC depends on environmental factors such as chronodisruption due to exposure to light at night i. The particular role of estrogens in the physiopathology of breast cancer explains why chemoprevention using any drug able to antagonize their actions would be taken into consideration [ 5 ].
The influence of estrogens on mammary tissue depends on the circulating levels of estradiol and other steroids as well as on their local concentration in mammary tissue. While the main source of estrogens in premenopausal women is the ovaries, in postmenopausal women adrenal androgens and sulfated estrogens are the primary circulating steroids, and these steroids are converted into active estrogens by enzymatic processes in the mammary tissue.
Figure 1 depicts the basic enzymatic mechanisms involved in the transformation of steroids in the mammary gland [ 26 ]. These estrogens, due to the action of estrogen sulfatases and estrogen sulfotransferases may be in two different forms: sulfated or not sulfoconjugated.
Estrogen sulfates can serve to form active non-sulfated estrogens [ 28 ]. Contrary to what happens in normal mammary tissue, in breast cancer, the local production of steroids is biased toward the production of the more active forms a fact indicated by the thickness of the arrows in Figure 1 [ 26 ].
The basic enzymatic mechanisms involved in the transformation of steroids in the normal mammary gland and in breast cancer tissue. Melatonin acts as a selective estrogen enzyme modulators SEEM by inhibiting the expression and activity of the enzymes labeled in red responsible for the formation of biologically active estrogens from steroids with low biological activity, whereas it increases the expression and activity of the enzymes labeled in green involved in the transformation of estrogens into their inactive sulfoconjugates.
In breast cancer tissue, the local production of steroids is biased towards production of the more active forms wide arrows. Selective estrogen receptor modulators SERMs are drugs that are able to bind to the ER and act as estrogen antagonists in the uterus and breast. Flushes, as well as increased risk of pulmonary embolism and endometrial cancer are adverse effects described as being associated with treatment with tamoxifen [ 32 ].
A comparative clinical trial between tamoxifen and raloxifene has shown that, although the first appears to be more effective than the second, in terms of reducing BC risk, the undesirable side effects related to tamoxifen, particularly the increased risk of endometrial cancer, are lower in women treated with raloxifene [ 33 ].
A second family of antiestrogenic drugs includes the selective estrogen enzyme modulators SEEMs , that is to say, drugs that do not bind to the ER but instead modulates the activity of the enzymes involved in the conversion of androgens into estrogens, as well as those involved in the interconversion between inactive conjugated and active unconjugated steroids.
Exemestrane and anastrozole are drugs belonging to the SEEM family, and both have antiaromatase properties. Their efficacy in reducing the risk of BC in postmenopausal women has been demonstrated in different clinical trials [ 5 ].
Furthermore, melatonin increases the expression and activity of estrogen sulfotransferases, thus favoring the transformation of estrogens into their inactive sulfoconjugates Figure 2 [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ].
Summary of the evidence supporting the role of melatonin as a possible adjuvant therapy with other selective estrogen enzyme modulators SEEM and selective estrogen receptor modulators SERM drugs to reduce the risk of breast cancer.
Melatonin not only has both SEEM and SERM properties, it also enhances the effectiveness of other antiestrogenic drugs while reducing or preventing their unwanted side effects. In addition to its simultaneous properties functioning as both a SEEM and a SERM, experimental data has also revealed that melatonin increases the sensitivity of MCF-7 cells to the effects of antiestrogens such as tamoxifen [ 49 ], and that pretreatment with melatonin increases the reduction of aromatase expression and the activity of cells exposed to aminoglutethimide, an anti-steroid drug [ 50 ].
Furthermore, melatonin could be also useful for reducing or suppressing some of the side effects of conventional antiestrogens Figure 2.
In this regard, it has been demonstrated, in animal models, that melatonin reduces the hepatotoxicity of the aromatase inhibitor letrozole [ 51 ]. A recent patent US; , from Witt-Enderby et al. In mice, the administration of the hybrid compound N -desmethylhydroxytamoxifen-melatonin showed anticancer effects without the uterine hyperproliferation observed after treatment with tamoxifen alone.
These results have not yet been published in ordinary scientific journals. Interestingly, the possible association of melatonin with antiaromatases could reduce the risk of osteoporosis described with treatment with this family of drugs. Melatonin promotes osteoblast proliferation and the synthesis of osteoprotegerin, a member of the tumor necrosis factor receptor TNFR superfamily.
In this way, melatonin could cause an inhibition of bone resorption and an increase in bone mass [ 52 , 53 , 54 , 55 ]. In addition, the osteoclastic activity generates free radicals that induce bone degradation and resorption [ 56 ]; melatonin may reduce the osteoclastic activity by neutralizing free radicals and stimulating the activity of antioxidant enzymes [ 56 , 57 ]. The usefulness of melatonin in the treatment of osteoporosis has been analyzed in several clinical trials carried out in postmenopausal women with osteopenia.
The role of melatonin in bone metabolism is also supported by indirect data such as the association between the incidence of hip and wrist fractures and nightshift work which suppresses melatonin production in postmenopausal nurses [ 60 ], and between the increased incidence of osteoporosis and the decrease of melatonin production with age [ 61 ].
A meta-analysis of 51 epidemiological studies comprising more than The patent documents described experiments carried out on mice, concluding that associating melatonin with HRT significantly increases the latency and decreases the incidence of mammary cancer. In conclusion, the above-mentioned data strongly supports the possible benefits of the association of melatonin with conventional antiestrogens as well as HRT to reduce the risk of BC, and clinical trials to analyze the efficiency of these cotreatments are encouraged.
The link between BC risk and environmental factors is a subject of growing relevance [ 63 ]. There is one environmental factor that, in our opinion deserves special consideration: the chronodisruption induced by the exposure to light-at-night LAN , particularly short wavelength light i. The reason is the growing number of individuals involved in nocturnal shift work.
A second group of environmental factors related to BC risk includes chemical contaminants present in food, pharmaceutical agents and cosmetics, or due to occupational exposures, etc.
Circadian rhythm disruption induces alterations in one hallmark of cancer, cell division, thus contributing to cancer progression, and the pharmacological modulation of proteins related to clock genes is being considered as a possible strategy for cancer treatment [ 64 , 65 ]. The administration of melatonin could reduce the breast cancer risk associated with chronodisruption caused by exposure to light at night, such as occurs in nocturnal shift workers.
The exogenous melatonin restores the decreased circulating levels of the endogenous hormone, caused by nocturnal light, and regulates the function of the circadian system. That LAN increases the rate of growth of mammary tumors has been solidly established in experiments carried out in rodents with chemically induced tumors or xenografts of cancer cells [ 66 , 67 ].
Furthermore, mutant mice prone to developing mammary tumors, increased their risk of developing such tumors when exposed to chronically alternating light cycles simulating a shift work [ 68 ]. The association between shift work including night work and the increased risk of different kinds of cancer is supported by numerous studies [ 64 , 69 , 70 , 71 ], although the mechanisms underlying this relationship are still under study.
The potential impact of shift work in breast cancer has been estimated at a population attributable fraction of 5. Epidemiological studies, despite some controversies, support the relationship between long-time night shift work and an increased risk of breast cancer [ 63 ]. Based on this classification, the National Board of Industrial Injuries in Denmark has recognized BC as an occupational disease, in women that had been doing night shift work for at least one day per week over 20 or more years.
Consequently, these women, mainly nurses and flight attendants, received an economical compensation from the Danish government [ 74 ]. There are, however, discrepancies about the carcinogenic effects of nocturnal work, and several epidemiological studies conclude that night shift work has little or no effect on breast cancer incidence [ 75 ]. These discrepancies may be related to methodological differences between the studies, due to the complexity of this kind of analysis [ 63 ].
The most recent published review on this subject concluded that there is a tendency toward an increased risk of BC among women after 20 or more years of shift work or even after shorter periods involving many consecutive shifts [ 77 ].
The two most widely accepted explanations for the biological effects of LAN in elevated BC risk are: the light-induced inhibition of melatonin secretion, with the subsequent loss of the SEEM and SERM effects of this neurohormone; and alterations to the circadian system chronodisruption induced by exposure to nocturnal light [ 15 , 39 , 40 , 41 , 42 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ].
Regarding the influence of decreased melatonin secretion, a relationship between low plasma melatonin concentration and breast cancer was described as early as by Cohen et al. These authors coined the expression "relative hyperestrogenism" to define the hormonal situation of women with low melatonin secretion, whatever its cause.
Postmenopausal women working at night have elevated serum estradiol levels and a significant decrease in urinary excretion of 6-sulfatoxymelatonin aMT6s , a metabolite of melatonin that serves as an indicator of melatonin secretion [ 86 , 87 , 88 ].
The coupling between the cellular clocks and the cell cycle is the key to explaining the relationship between chronodisruption and cancer [ 89 , 90 ]; the disruption of the circadian rhythms induced by LAN can cause alterations in the cell cycle and lead to the development of tumors [ 91 , 92 ].
However, despite the experimental and epidemiological evidence regarding the role of LAN in mammary carcinogenesis, the benefit of melatonin supplementation in women working at night is still yet to be assessed.
Among the environmental factors with possible incidence in BC risk, the role of chemical contaminants is a matter of discussion, although there is general agreement that environmental estrogen-like compounds xenoestrogens could be related to the onset and development of BC [ ]. Currently, more than xenoestrogens potentially involved in BC development have been identified [ ].
Cadmium, a metalloestrogen, increases the risk of breast cancer by stimulating cell proliferation due to its estrogenic properties, as well as by producing oxidative stress through mitochondrial damage. Melatonin could reduce the risk of breast cancer in individuals exposed to Cd from contaminated food, smoke, or occupational hazards. Furthermore, melatonin downregulates the hTERT expression induced by Cd and increases the synthesis of metallothioneins, which are proteins involved in Cd detoxification.
Moreover, melatonin prevents against Cd-induced oxidative stress. Cd is naturally present in soils, sediments, seawater, plants, and animals and is a food-chain contaminant. Due to its long biological half-life Cd accumulates in the body [ ].
Because of this high exposure prevalence, any increase in risk of disease from Cd would result in a large number of affected individuals [ ]. Although the kidneys are the organs most affected by Cd exposure, epidemiological studies have demonstrated that this metal can increase the risk of BC [ , , , , ]. The concentration of Cd in the blood [ ] as well as in the urine a measure of cumulative lifetime Cd of BC patients is significantly higher than in healthy controls [ , , , ], and a positive correlation between Cd content in breast tumor tissue and the histological type of tumor, its size, grading and progesterone receptor status, has been described [ , ].
There are, however, other studies that showed no association between urinary concentration of Cd and risk for development of BC [ , ]. There are two basic explanations for the effects of Cd on the mammary gland. One, is related to the estrogenic effects of this metal. In vivo, Cd activates the genomic and non-genomic ER pathways in mammary glands [ ]. The second reason for the damaging effects of Cd is related to its ability to induce oxidative stress.
Although Cd does not produce radicals in Fenton type reactions, it induces oxidative stress through the reduction of antioxidative defenses as well as by the production of reactive oxygen species through mitochondrial damage [ ].
Melatonin exerts remarkable actions against the estrogenic effect of Cd. Furthermore, melatonin down-regulates the Cd-induced expression of hTERT, the telomerase subunit main determinant of its enzyme activity [ ]. In vivo, melatonin prevents the estrogenic effects of Cd on mice mammary glands and uterus [ ].