Comments by Virginia Hopkins

The Science of Melatonin, an Essential Hormone

Below are just a few of the hundreds, if not thousands of studies published about melatonin, with more coming out every week. These are some of the most important studies, as well as those that apply to our daily lives, and in particular, nightly life.

The most important way to maintain normal melatonin levels is to get plenty of sleep in a dark room. Even night shift workers can produce enough melatonin if they sleep in darkness. Please see the “Related Articles” links below for more information about melatonin, including recommendations for when and how to use melatonin supplements.

Melatonin Affects Male Fertility

Awad H, Halawa F et al, “Melatonin hormone profile in infertile males,” Int J Androl 2006 Jun;29(3):409-13.
Researchers measured melatonin levels in semen and serum (blood) in both fertile and infertile men. They found a direct correlation between low melatonin and infertility, as well as sperm motility. From this and other studies we can conclude that low melatonin levels in men can reduce their fertility and may even cause infertility.

Melatonin and the Ovaries

Woo MM, et al, “Direct action of melatonin in human granulosa-luteal cells,” J Clin Endocrinol Metab 001 Oct;86(10):4789-97.
Woo et al found that melatonin acts as a modulatorof ovarian function. Melatonin enhances human chorionic gonadotropin-stimulated progesterone production, LH receptor mRNA levels, GnRH, and GnRH receptor gene expression. This correlates well with the finding that working night shifts in a brightly lit environment leads to estrogen dominance and a 60 percent increase in the risk of breast cancer.

Nakamura Y, Tamura H, “Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production,” Fertil Steril 2003 Oct;80(4):1012-6.
Melatonin is synthesize in many places in the body besides the pineal gland, including in the ovaries. Japanese researchers found that pre-ovulatory follicles (those about to “pop” and become eggs traveling down the tubes) contained higher amounts of melatonin than smaller, more immature follicles. They theorize that melatonin may play a role in progesterone production, but does not directly influence it.

Melatonin and Breast Cancer

A. Gonzalez, S. Cos, et al, “Selective estrogen enzyme modulator actions of melatonin in human breast cancer cells, J Pineal Res, 2008 Feb 19 [Epub ahead of print]
Researchers in Spain researched the mechanisms by which melatonin inhibits the growth of breast cancer cells in estrogen-responsive pathways. They found that melatonin inhibits the expression of estrogen in breast tissue along multiple enzyme pathways.

Schernhammer ES, Hankinson, “Urinary melatonin levels and breast cancer risk,” Journal of the National Cancer Institute, 2005 Jul 20;97(14):1084-7.
This research is an ongoing part of the Harvard Nurses’ Study. They looked at melatonin concentrations by measuring the hormone in the first urine void of the day. They found that over time, women with the highest melatonin levels had the lowest risk of breast cancer.

Verkasalo PK, Lillberg K et al, “Sleep Duration and Breast Cancer: A Prospective Cohort Study,” Cancer Research 65, 9595-9600, October 15, 2005.
Finnish scientists looked at the possibility that lack of sleep, and thus lower melatonin levels, contribute to the risk of breast cancer. They looked at how long, on average women slept each night, and found that women who slept 9 hours or longer had a 30 percent decreased risk of breast cancer compared to women who slept less than six hours a night.

Night Shift Work Can Cause Low Melatonin and Increased Risk of Cancer

Way back in 1987, Richard Stevens, now of the University of Connecticut Health Center, published a study that suggested a link between night shift work and breast cancer. This was a brand new concept and he was summarily dismissed by other scientists in the field. Over time, other research has proven him right, and in December 2007 the International Agency for Research on Cancer, the cancer arm of the World Health Organization, officially classified working night shifts as a “probable” carcinogen.

According to William Hrushesky of Dorn Veterans Affairs Medical Center in Columbia, S.C., female night-shift workers have about a 50 percent greater risk of developing breast cancer.

In Feb 2008, the journal Chronobiology International published a study by scientists at the University of Haifa in Israel linking bright lights at night to breast cancer. They used satellite imagery to compare brightness at night in various cities and towns in Israel with the prevalence of breast cancer. They found a significant correlation—the brighter the lights, the higher the risk of breast cancer: when they compared communities with the lowest amount of light to average communities, they found 37 percent higher breast cancer rates, and communities with the highest amount of lighting had a whopping 64 percent higher rate than the lowest.

Melatonin and Cancer

Mills E, Wu P et al, “Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis,” J Pineal Res 2005 Nov:39(4):360-6.
These researchers analyzed the data from studies where cancer patients were treated with melatonin and concluded that on average they had a 24 percent reduced risk of death. They state that, “The substantial reduction in risk of death, low adverse events reported and low costs related to this intervention suggest great potential for melatonin in treating cancer.”

Melatonin’s Diverse Effects on the Body

Reiter RJ, Tan DX et al, “Medical implications of melatonin: receptor-mediated and receptor-independent actions,” Adv Med Sci. 2007;52:11-28.
This is an overview of melatonin’s functions in the body. The authors note that, “The functional versatility and diversity of melatonin has exceeded everyone's expectations. The evidence is substantial that melatonin has multiple receptor-mediated and receptor-independent actions. … melatonin likely functions in every cell with which it comes in contact. In addition to its widespread actions, melatonin synthesis occurs in widely diverse tissues with its production not being relegated to the pineal gland. [Some] …functions include the control of seasonal reproduction, modulation of sleep processes and influences on bone growth and osteoporosis…, …ability to neutralize free radicals which leads to a reduction in cataract formation, reducing oxidative stress due to exposure to hyperbaric hyperoxia, ameliorating hyperthyroidism and abating the toxicity of sepsis and septic shock.” In other words, we’re only just beginning to understand the importance of melatonin in the human body.

Melatonin and Epilepsy

Fauteck JD, Schmidt H, “Melatonin in Epilepsy: First Results of Replacement Therapy and First Clinical Results,” Biol Signals Recept 1999;8:105-110.
German researchers found that 5 to 10 mg of melatonin helped epileptic children sleep better and reduced the frequency of epileptic attacks. Most research with melatonin and epilepsy has been done with children with severe epilepsy and other neurological problems. The outcomes have been inconsistent—in some children it helps, in others it doesn’t or even increases seizures. There are numerous anecdotal accounts of melatonin helping with epilepsy on the internet, but parents of children with epilepsy who want to try melatonin should probably work with a doctor.

Melatonin and Obesity

Robeva R, Kirilov G, “Melatonin-insulin interactions in patients with metabolic syndrome,” J Pineal Res 2008 Jan;44(1):52-6.
This is a great little study from Bulgaria, where researchers were trying to tease out the possible causes behind metabolic syndrome, the collection of symptoms that includes obesity, insulin resistance, high LDL cholesterol and triglycerides, and an increased risk of diabetes and heart disease. They looked at melatonin levels, and compared them with cholesterol and insulin levels in both normal patients and those with metabolic syndrome. They found little correlation in normal patients, but significantly lower melatonin levels in patients with high insulin and high LDL cholesterol. They theorize that, “The thrifty genotype in some patients and especially the permanent winter metabolism resulting in a strong fat storage and energy preservation could be a result of a desynchronized circadian and circannual melatonin rhythm. In those cases, the synchronization of biologic clock could have beneficial effects on the development and the consequences of the metabolic syndrome.”

Melatonin and the Prostate

Sainz RM, Mayo JC et al, “Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism,” Prostate 2005 Apr 1;63(1):29-43.
This test tube study done at the University of Texas Health Science Center showed that melatonin dramatically reduced the ability of prostate cells to differentiate and proliferate and point out this needs to be investigated further because melatonin levels are so reduced in older men who have the highest risk of prostate cancer. This is one of dozens of studies with similar results. Rodent studies with melatonin have shown it to be preventive and protective. Predictably, since melatonin is a natural substance that can’t be patented, the response has been for the pharmaceutical companies to scramble to invent pseudo-melatonins not found in nature that have similar effects.

Drake MJ, Mills IW, Noble JG, “Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement,” J Urol 2004 Mar;171(3):1199-202.
This was a small study out of the U.K. with only 20 men, but it was a double-blind crossover study. It looked at men with benign prostatic enlargement who took 2 mg of controlled release melatonin at night and evaluated the improvement of nocturia (getting up at night to urinate). Those taking melatonin did have a less nocturia and were less bothered by the episodes they did have.

Melatonin Supplementation and Male Hormones

Luboshitzky R, Levi M et al, “Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men,” Hum Reprod 2000 Jan;15(1):60-5.
Researchers in Israel measured LH, FSH and testosterone in 6 healthy men, gave them 6 mg of melatonin daily for one month, and then measured their hormones again. They found no change in hormone levels or secretory patterns caused by the melatonin supplements.