• Leo Rex

I'm on HRT Too: The Case for Melatonin

Updated: Sep 14

Citations for my review on melatonin follow. You can watch the video here.


INTRODUCTION


A. Melatonin was first isolated from a cow’s pineal gland tissue in 1958 by Aaron Lerner[1].


B. Melatonin is a very ancient molecule: it is produced by vertebrates, invertebrates, fungi, algae, and unicells[2].


C. Humans have two G protein-coupled melatonin receptors named MT1 and MT2, first identified by Reppert[3] et al. These receptors are found in the retinas[4], across the brain[5], in the adrenal cortex[6], in reproductive organs[7], in the cardiovascular system[8], and in organs that modulate immune function[9].


D. MT1 activity is associated with suppression of neuronal firing in the suprachiasmatic nucleus (SCN) whereas MT2 activity is associated with circadian phase shifts[10], and the density of these receptors varies according to the circadian rhythm[11].


E. In addition to its dedicated receptors, melatonin also binds to quinone reductase 2[12], calmodulin[13], calreticulin[14], the retinoic acid and retinoid x receptors[15], and in brain mitochondria[16].


F. Melatonin is metabolized extensively, with some of its metabolites (e.g. AMK[17]) having an even greater antioxidant potential than melatonin[18].


G. Summary of some effects: By improving circadian rhythms, melatonin suppresses oxidative damage. Melatonin prevents excitotoxic calcium overload in the nervous system. Melatonin modulates the immune system. Melatonin downregulates steroid receptors such as the glucocorticoid receptors, preventing apoptosis. Melatonin downregulates nitric oxide formation. In pharmacologic doses, melatonin potently neutralizes reactive oxygen and reactive nitrogen species, terminating radical reactive chains. See citation for a great overview[19].


MELATONIN AND THE BRAIN


A. Melatonin has neurotrophic effects. It co-localizes with the expression of BDNF and GDNF in some cells[20][21] and to stimulate their expression in stem cells, allowing them to diversify into mature cells[22].


B. For a review of melatonin’s neuroprotective character, see this citation[23].

C. There is much evidence for melatonin being particularly neuroprotective against the pathology of Parkinson’s disease[24].


D. Melatonin is being investigated for the treatment of Alzheimer’s disease (see this amazing review[25]).


E. Melatonin appears particularly useful for alleviating methamphetamine toxicity[26]. It may do the same for alcohol[27] (not just in the brain[28]).


MELATONIN AND AGING


A. Pharmacologic melatonin may improve aging[29].


B. Melatonin delays senescence[30].


C. Melatonin modulates sirtuin activity[31][32][33].


MELATONIN AND BLOOD PRESSURE


A. A meta-analysis of 5 controlled trials found that supplemental melatonin significantly reduced systolic and diastolic blood pressure[34]. This falls in line with theoretical evidence for melatonin and angiotensin modulating each other[35].


MELATONIN AND LIPIDS


A. A meta-analysis of 8 randomized controlled trials found that melatonin supplementation produced a large and significant reduction in serum triglycerides and a significant reduction in total serum cholesterol[36].


MELATONIN AND THE IMMUNE SYSTEM


A. Melatonin is immunomodulatory. It is synthesized by lymphocytes and the thymus. It stimulates natural killer cells and governs the release of T-helper 1 cells, B lymphocytes, and cytokine release[37].


B. In a randomized, double-blind, controlled study, 6 mg of melatonin reduced the TNF-alpha, interleukin-6, and C-reactive protein of obese women, indication a reduction in inflammation and oxidative stress[38].


MELATONIN AND CANCER


A. Melatonin is known to inhibit cancer development[39] and cancer metastasis[40].

B. Melatonin selectively triggers apoptosis in a variety of cancer cells[41].


C. Melatonin has been shown to inhibit breast cancer development, and it is thought that the reason night shift workers develop breast cancers more frequently is due to reduced melatonin synthesis[42].


D. Melatonin produces an anti-angiogenic effect by inhibits VEGF in liver cancer cells[43].


MELATONIN, INSULIN RESISTANCE, DIABETES, OBESITY, AND NAFLD


A. Melatonin regulates insulin sensitivity, producing insulin sensitivity early in the day and inducing insulin resistance when it is transmitted in the latter day[44]. It also influences GLUT4 expression, lipolysis, lipogenesis, fatty acid uptake, pancreatic islet function, and modulates IGF-1 activity.


B. A randomized, double-blind controlled trial found that 6 mg of melatonin significantly but minorly improved HbA1c, fasting blood glucose, and HDL-cholesterol among type 2 diabetics[45].


C. A randomized, double-blind controlled trial found that 10 mg of melatonin significantly improved insulin sensitivity, HDL-cholesterol, systolic and diastolic blood pressure, C-reactive protein, and metrics of oxidative stress among type 2 diabetics with coronary heart disease[46].


D. In a randomized, controlled trial, 10 mg of melatonin improved body weight reduction, antioxidant defense, and adipokine (cytokines released from adipose tissue, like leptin) secretion among obese dieters[47].


E. In a double-blind, controlled, crossover study, 8 mg of melatonin significantly improved some metrics of the metabolic syndrome[48].


F. Melatonin is particularly attractive for nonalcoholic fatty liver disease[49] and liver injury[50][51]. In a randomized, controlled trial, 10 mg of melatonin improved liver grade and C-reactive protein among sufferers of nonalcoholic fatty liver disease[52].


THOUGHTS FOR A PROTOCOL


A. At higher doses, melatonin becomes profoundly neuroprotective[53].


B. High doses protect against cardiac ischemia-reperfusion injury[54].


C. 300 mg of rectal melatonin was successfully used to normalize oxidative damage in a group of 31 ALS patients[55].


D. 50 mg of oral melatonin was well-tolerated in a study on Parkinson’s patients[56].


E. Oral melatonin has a:


a. 15% average absolute bioavailability[57]. The low bioavailability is due to extensive first-pass metabolism[58].


b. One study found 2 mg of melatonin reached peak concentrations in plasma/serum at 15 minutes while 10 mg did in 210 minutes[59]. Another study found the peak concentration of 10 mg of melatonin at 41 minutes with a half-life of 54 minutes[60].


F. Oral extended-release melatonin has a[61]:


a. 10-56% absolute bioavailability with an average of 15%.


b. Half-life of 3.5-4 hours.


c. A maximum serum concentration at 0.75-3 hours.


d. 60% of it binds to proteins, mainly albumin, alpha1-acid, and HDL


e. Is metabolized by CYP1A1, CYP1A2, and potentially CYPC19.


f. Its affinity for MT1 is 0.081 Ki (nM) and MT2 is 0.383 Ki (nM).


G. Interestingly, high-dose intravenous administration has been studied[62], as has low-dosed intranasal administration[63]. Transdermal and oral transmucosal administration has also been studied[64].


a. Intravenous melatonin has a linear elimination graph[65].


H. Intuitively, twice a day dosing appears to damage sex hormone production by interfering with gonadotropin releasing hormone[66].


I. It is believed that a loss of response to melatonin supplementation is due to slow metabolism, particularly, to reduced activity of the CYP1A2 enzyme (found in 12-14% of people)[67].

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