Melatonin Chronosynergy, Women, and Aging

 In Anti-Aging, Geriatrics, Women's Health

The Expert Report
Interview with Paula Witt-Enderby, PhD and Judith Balk, MPH, MD

Mark Swanson, ND

The concept of achieving therapeutic “synergy” is fundamental to the understanding of healing in a functional-naturopathic medicine practice. I have often postulated that there is a single universal therapeutic synergist—one that almost always “fits” the treatment protocol to further improve the outcome. Many would say that this attribute mostly belongs to omega-3 eicosapentaenoic acid/docosahexaenoic acid, while others may argue that vitamin D3 has become the optimal universal synergist. Worthy of an honorable mention too are glutathione, N-acetylcysteine, coenzyme Q10, and even curcumin. After much thought and research review, my nomination for this distinct honor goes to melatonin (N-acetyl-5-methoxytryptamine). The reasons, mechanisms, and therapeutic applications supporting this are well documented in more than 16 000 studies and are beyond the scope of this interview. I will simply say that melatonin is not just for sleep anymore.

With this in mind, my invited guests for The Expert Report this month are 2 distinguished melatonin research collaborators, Paula Witt-Enderby, PhD, and Judith Balk, MPH, MD. They candidly discuss their expertise and research on melatonin and how it may benefit women’s health, bones, and aging, as well as its use as a chronosynergistic agent. Note that both guests are contributing to the answers for each question unless noted otherwise.

What is your educational background and current position?

Paula Witt-Enderby, PhD: I received a BS in biochemistry from the University of Illinois (Urbana-Champaign) in 1988 and pursued doctoral studies at the University of Arizona [Tucson], where I received a PhD in pharmacology and toxicology in 1993. I continued on with postdoctoral studies in the department of molecular pharmacology and biological chemistry at Northwestern University Medical School [Chicago, Illinois] from 1993 to 1996. In 1996, I started my career as an assistant professor in pharmacology and toxicology at Duquesne University School of Pharmacy [Pittsburgh, Pennsylvania]. I was promoted to associate professor in 2002 and then to professor in 2008.1

Judith Balk, MPH, MD: I received a BA in biology from Washington University in St Louis, Missouri, in 1985. In 1989, I received an MA in public policy and management from the University of Pennsylvania, Wharton School of Business [Philadelphia]. From there, I pursued a degree in medicine from the University of Pennsylvania in 1990 and completed a residency in obstetrics and gynecology at Magee-Womens Hospital, University of Pittsburgh School of Medicine in 1994. I am board certified in acupuncture and holistic medicine and am certified as a Yoga Alliance teacher. I became an assistant research professor at the University of Pittsburgh School of Medicine in 1997, and in 2009 was promoted to associate professor.2

What led you to become involved with melatonin research? What has it mainly focused on?

Paula Witt-Enderby, PhD: Following my postdoctoral studies, I moved into the melatonin receptor field when the human receptor genes were cloned in 1994 and 1995. For 8 years, the research focus of my laboratory was to elucidate the molecular mechanisms governing cellular differentiation induced following chronic melatonin exposure. Through years of hard work by my graduate students, we discovered that a specific signal transduction cascade, or series of proteins within the cell, was responsible for melatonin’s differentiating effects in cells. We found melatonin was able to induce mesenchymal stem cells to become bone-forming cells, called osteoblasts. This is an important discovery since melatonin, long recognized to be involved in regulating sleep-wake cycles, is now shown to regulate bone-forming cells. In 2005, I met Dr Balk at the Hillman Cancer Institute, Pittsburgh, Pennsylvania, where she was speaking on functional medicine. We discussed our complementary research interests: my findings on melatonin and osteoblasts and her research on yoga and bone health.3 This led to our collaboration and completion of a clinical trial titled “Melatonin Osteoporosis Prevention Study” (MOPS) ( identifier NCT01152580) assessing the efficacy of melatonin in perimenopausal women.


What is the primary function of melatonin in the body? Is it different in women than in men?

Melatonin is synthesized in the pineal gland in response to dusk and darkness. Its primary function in the body is to entrain one’s circadian rhythms, or sleep-wake cycles, to the light-dark cycle, although it influences many organ systems. For the most part, melatonin produces similar effects in both men and women, with differences occurring in the absorption of melatonin. However, research is emerging (including in our recent study4) showing melatonin to have effects on regulating menstrual cycles.

Is there good hypothetical support for using various nighttime melatonin chronosynergy combinations with other natural agents that will have a greater clinical response advantage vs taking only the single agent during the day?

Yes, there is. Melatonin is a unique molecule because it can modulate pathways within a cell, triggered by activation of receptors in the plasma membrane or triggered by melatonin itself, since it can pass through membranes and enter the cell directly. Synergy between melatonin and drugs or natural agents has been shown to occur. The manner in which the melatonin synergy enhances a drug or natural product’s efficacy varies. Examples are enhancing a common intracellular signaling pathway or by each acting on complementary pathways which together would enhance the desired outcome. Studies show that nocturnal supplementation with melatonin is most efficacious, and the doses are tailored on an individual basis. Melatonin can also affect the half-life of certain drugs in the body or even reduce a drug’s efficacy by sharing similar metabolizing enzymes, so a staggering of the times of administration may be required with some agents.

Dr Swanson’s comment: Plausible examples are using melatonin in combination with strontium and vitamins D3 and K2 (D3/K2) for osteoporosis reversal, D3/K2 for insulin balance and coronary calcification, resveratrol and/or curcumin for cancer chemoprevention, and other agents for metabolic syndrome, weight loss, natural hormonal modulation, brain aging, longevity, neurological support, inflammation, etc. The list goes on.

What are the best evidence-based clinical applications for melatonin in women?

Melatonin is primarily known for its effects on jet lag and other circadian rhythm disturbances in both men and women. However, there is emerging evidence for a role of melatonin in improving circadian disturbances associated with menopause.

You just completed the MOPS, to be published in 2012, assessing the efficacy of melatonin in perimenopausal women. Tell us more about the study design, outcome, implications, etc.

This was a double-blind placebo-controlled trial designed to study the efficacy of melatonin (3 mg, PO, at bedtime) on bone health and symptoms associated with perimenopause. The primary outcome measure was melatonin effects on bone density and serum bone markers.

These results showed important trends towards a normalization of bone marker (osteoclast-osteoblast) activity. The secondary outcome measure was sleep and menopause quality of life, assessed with validated questionnaires and daily diaries. After 6 months’ melatonin (3 mg, PO, at bedtime), subjects reported significant improvements in physical symptoms of menopause compared to women taking placebo. The mean number of menstrual cycles with melatonin was significantly less, and the mean days between cycles was significantly longer also. With physical symptoms, we think women were feeling better because they were sleeping better, though no significant difference in sleep quality via a questionnaire was reported. There were no differences between melatonin use on the duration of bleeding, vasomotor symptoms, or psychosocial or sexual well-being compared to placebo. This study will be published in the Journal of Pineal Research in 2012.

Why was a perimenopause group chosen vs menopausal women or women with osteoporosis?

If proven efficacious, the implication for this therapy would be an alternative therapy for preventing osteoporosis. It is during perimenopause when women begin to experience bone loss.

Dr Swanson’s comment: Randomized double-blind placebo-controlled trials are needed to answer the question whether melatonin can be considered a treatment option for increasing bone formation and bone density, reversing bone loss, and preventing new fractures in women with osteoporosis. Our clinical outcomes with the Fully Optimized Osteoporosis Therapy (FOOT)4,5 plan support a positive effect.

Does melatonin protect against breast cancer?

Melatonin has numerous actions within the cell that could contribute to its anticancer effects, including its ability to slow down cell growth, scavenge free radicals, reduce levels of estrogen, and enhance cell adhesion. The research studies, reviews, and books published on this aspect of melatonin on breast cancer and the data are exciting and important.

Is melatonin a useful adjuvant therapy for treating breast cancer?

Our research group recently contributed a book chapter entitled “Prevention and Treatment of Breast Cancer Using Melatonin,”6 where we discuss ways in which clinicians could use melatonin in their practice to prevent and/or treat breast cancer in women. We discuss how it can be used alone possibly to prevent breast cancer in those at risk and ways it can be combined with other hormone therapies, specifically aromatase inhibitors and selective estrogen receptor modulators (SERMs), to enhance their mechanism of action.

Help us understand the differences between melatonin receptor–dependent action and receptor-independent actions of melatonin.

Melatonin is a lipophilic molecule that can act on melatonin receptors located in the plasma membrane of a cell, or it can pass through membranes and bind to proteins to direct cellular events. Melatonin can scavenge free radicals produced inside the cell and protect the cell from damage at the protein, RNA, and DNA level.

Is there any clinical value for measuring melatonin levels in an integrative women’s care setting for determining health status and treatment options?

A dampening of the nocturnal surge in melatonin through age, changes in hormonal status, and/or light exposure at night may contribute to diseases like cancer and osteoporosis. Therefore, assessing one’s nocturnal levels of melatonin and supplementing these nocturnal levels back to levels in the normal range (80-100 pg/mL) may prove to be beneficial in one’s health, although the data are lacking.

Could the chronobiology effects of melatonin on sleep quality be considered a necessary baseline target event for achieving outcomes of all the other clinical applications of melatonin?

Yes, restoring circadian rhythm disturbances induced by many conditions (eg, depression, use of antihypertensives, use of hormonal anticancer therapies, aging, etc) could improve health outcomes by improving overall well-being.

Are there advantages to using prolonged-release vs immediate-release melatonin? What is a reasonable dose in most applications besides cancer?

Most over-the-counter melatonin supplements range in dose between 1 and 5 mg. However, many of the cancer studies have used doses much higher (8-20 mg). Prolonged-release melatonin mimics more closely the rhythm of melatonin, and people may respond better to that formulation over others. However, each person may respond differently to melatonin, so the dose and formulation should be tailored to the individual.

Dr Swanson’s comment: A recent study7 in mice suggests that prolonged-release melatonin improves vessel endothelial cytoarchitecture to a greater extent than rapid-release melatonin.

Is there any indication where melatonin should be taken during the day or away from bedtime?

It depends on what melatonin is being used for. Because melatonin is a strong free radical scavenger, the formation of free radicals and their resultant toxicities could be minimized by giving melatonin right before or in combination with therapies that cause free radical production. Again, this should be done in consultation with one’s physician, as this area is controversial.

Are there any safety or adverse effect issues with melatonin to be concerned with?

In most of my readings on its safety profile, as well as our experience running the MOPS, melatonin is shown to be relatively free of side effects. Most common is sleepiness and grogginess. When taking other drug therapies, it could modulate a drug’s response in the body (desired or not desired), as stated above. As with any therapy, caution should always be taken with its use especially if one is pregnant.

Dr Swanson’s comments: Studies8,9 have shown that melatonin is very safe and well tolerated across a wide variety of patients, applications, and dosages—including children and the elderly, diabetes, immune and neurological disorders, depression, insomnia, cancer, cardiovascular disease, and hypertension—and does not cause withdrawal symptoms or suppress endogenous production.

Dr Swanson’s closing comments:

The emerging concept of melatonin’s chronosynergy is an intriguing one, with a growing trend in the scientific literature supportive of this. I would like to thank Paula Witt-Enderby, PhD, and Judith Balk, MPH, MD, for providing a brief but informative glimpse of melatonin as a therapeutic agent for women’s health and aging and its possible chronosynergy for achieving greater outcomes with common treatment protocols.

Mark Swanson, ND, writes “The Expert Report” column, which is featured in NDNR.  Dr. Swanson has over 25 years experience as chief medical advisor, research and technical consultant, and products formulations expert to leading practitioner brand supplement manufacturers.  He is a former associate editor for the American Journal of Naturopathic Medicine, national product director, and published researcher. He is a pioneer graduate of Bastyr University, 1984.  Dr. Swanson has his private practice specializing in Preventics Care and Functional Medicine, in Sequim, Washington. Contact: [email protected]



1. Mylan School of Pharmacy. Division of Pharmaceutical Sciences: faculty. Accessed December 19, 2011.

2. University of Pittsburgh. Department of Obstetrics, Gynecology & Reproductive Sciences: faculty. Accessed December 19, 2011.

3. Balk J, Bernardo LM. Using yoga to promote bone health and reduce fracture risk in the geriatric population. Top Geriatr Rehabil. 2011;27:116-123.

4. Swanson M. The FOOT plan: the natural osteoporosis cure. NDNR. February 2008.

5. Swanson M. The FOOT plan: osteoporosis therapy update and outcomes. NDNR. August 2010.

6. Davis VL, Dodda BR, and Witt-Enderby PA. Prevention and treatment of breast cancer using melatonin. In: Watson RR, ed. Melatonin in the Promotion of Health. 2nd ed. Boca Raton, FL: CRC Press; 2011.

7. Rodella LF, Favero G, Rossini C, et al. Aging and vascular dysfunction: beneficial melatonin effects [published online ahead of print November 23, 2011]. Age (Dordr). doi:10.1007/s11357-011-9336-z. Medline:22109832

8. Lemoine P, Garfinkel D, Laudon M, Nir T, Zisapel N. Prolonged-release melatonin for insomnia: an open-label long-term study of efficacy, safety, and withdrawal. Ther Clin Risk Manag. 2011;7:301-311.

9. Garfinkel D, Zorin M, Wainstein J, Matas Z, Laudon M, Zisapel N. Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab Syndr Obes. 2011;4:307-313.

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