Melatonin's effect on height

Melatonin is known as a sleep compound which has led some to believe that melatonin can be used to increase height by virtue of increasing growth hormone levels.  Growth Hormone has had relatively lackluster benefits on increasing height due to the fact that chondrocytes have a finite proliferative capacity.  Now, IGF-1 may increase stem cell proliferation thereby increasing height that way and increase excretion of extracellular matrix. Growth hormone may help increase height in the top of the head and the heel bone, two bones which grow differently than long bones and two bones that influence height.  However, to grow taller the best way is to get stem cells to differentiate into chondrocytes forming new growth plates.  Melatonin is produced within the bone marrow which contains mesenchymal stem cells.  Can Melatonin help increase height? 

Osteogenic differentiation of rat mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells: melatonin as a differentiation factor. 

"We assayed and compared the melatonin effect on osteogenic differentiation of BMSC with that of ADSC. Mesenchymal stem cells (MSC) were isolated from the bone marrow and fat of adult rats. Both cell types were cultured in osteogenic medium in the absence and presence of melatonin at physiological concentrations (20-200 pg/ml). After 4 weeks, the expression of osteocalcin gene was analyzed by reverse transcription-PCR, alkaline phosphatase (ALP) activity was assayed and alizarin red S and von Kossa staining were done. Cell viability and apoptosis were also assayed by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, a tetrazole (MTT) and flow cytometry, respectively. The osteoblastic differentiation of ADSC as demonstrated by ALP activity was less than that of BMSC. The amount of matrix mineralization showed statistical differences between the two MSC. The incidence of apoptotic cells was higher among ADSC than BMSC. Cell growth reduction is due to a decrease in the number of the cells entering the S phase of the cell cycle. Viable cells were fewer among ADSC than BMSC in control groups.  BMSC have greater osteogenic potential than ADSC and melatonin promotes osteogenic differentiation to BMSC, but has a negative effect on ADSC osteogenic differentiation." 

If Melatonin discourages adipogenic differentiation then chondrogenic differentiation becomes more likely. 

A new guest playing with bone and fat 

"Hypoxia reduces MSC adipogenic differentiation through the hypoxia-inducible factor-1alpha transcription factor. Superoxide dismutase (SOD)-deficient mice show spontaneous adipogenesis. The redox balance in bone marrow may induce differentiation of MSC cells toward osteogenesis or adipogenesis, suggesting a role for oxygen free radicals in these regulatory pathways. Nitric oxide derivatives of linoleic acid are also potent adipogenic agonists in the physiological range, and they can inhibit osteogenesis through PPAR-Y receptors. The free radical scavenging properties of melatonin against oxygen and nitrogen reactive species, and its ability to induce expression of antioxidative enzymes, including SOD, may underline its ability to guide the MSC differentiation toward osteogenesis{Melatonin may alter the oxygen and nitrogen reactive species balance, however some of those are important for height growth but you don't want left over reactive species hanging around and causing potential damage}. The relationship among age, oxidative stress, osteopenia, and adipocyte accumulation in the marrow cavity seems clear. Senescent-accelerated mice (SAM) mice, a murine strain of accelerated senescence and oxidative stress, show osteopenia and high levels of PPAR-Y mRNA. Melatonin prevents the age-dependent oxidative stress and inflammation in SAM mice, suggesting that the significant decay in melatonin production with age may favor the adipogenetic pathway of MSC differentiation."

So essentially melatonin combats oxidants which have the potential to harm DNA and encourages mesenchymal stem cells to differentiate away from adipocytes therefore being more likely to differentiate into chondrocytes. Melatonin is naturally produced by the body, however, melatonin levels decrease with age and perhaps as shown by how much infants sleep maybe very radically. 

"Melatonin [interacts] with cytosolic calcium-calmodulin complex, modifying many of the calcium-calmodulin-dependent enzymes, including the nitric oxide synthase and nitric oxide production{Calcium and Nitric Oxide pathways are important for height growth}. Melatonin [scavenges] free radicals, yielding a series of metabolites with significant physiological activities{Melatonin may take free radicals and turn them into useful metabolites with possible height increasing effects}"

Even though this paper was about Melatonin encouraging osteogenic differentiation, it illustrates the interaction of Melatonin with Calcium and Nitric Oxide pathways both of which are involved in height growth.

Melatonin has an effect on chondrocytes... 

The effect of exogenous melatonin administration on trabecular width, ligament thickness and TGF-beta(1) expression in degenerated intervertebral disk tissue in the rat. 

"Degenerative changes in IVD [intervertebral disc disc] tissue affect the adjacent vertebral structure, resulting in a decreased vertebral trabecular width. It has been suggested that transforming growth factor-beta 1 (TGF-beta(1)) may have a role in the repair of connective tissue, as it occurs in the IVD degeneration process. In this study, we investigated the effects of exogenous melatonin (MEL) administration on vertebral trabecular width, ligament thickness and TGF-beta(1) expression in degenerated IVD tissue. Fifteen adult male Swiss Albino rats were divided randomly into three groups; nonoperated control, operated degeneration, and MEL treatment groups. In the operated degeneration and MEL treatment groups, cuts were made parallel to the end plates in the posterior annulus fibrosus at the fifth and tenth vertebral segments of the tail to induce IVD degeneration. In each group, TGF-beta(1) immunoreactivity and morphometry of vertebral trabecular width and anterior and posterior ligament thickness were evaluated. Histologically, disorganisation and irregularity of collagen fibres was seen in the degenerated (operated) IVD. Increased TGF-beta(1) expression in multinuclear chondrocytes was also observed as was decreased vertebral trabecular width. Importantly, the reduction of trabecular width observed in the operated degenerated group was reversed after MEL administration (p<0.0001). Similarly, TGF-beta(1) expression in multinuclear chondrocytes was dramatically increased after exogenous MEL application. Thus, there was a regression in histopathological changes after MEL treatment, with disk appearances similar to those of the control group. Based on our findings, we suggest that MEL activates the recovery process in the degenerated IVD tissue, possibly by stimulating TGF-beta(1) activity. This is the first report investigating the involvement of the pineal hormone MEL in the repair of rat IVD." 

Melatonin increases TGF-Beta 1 levels which affect the chondrocytes.  TGF Beta is an essential part of chondrogenesis. 

"MEL levels are characteristically high at night and low during the day. Interestingly, MEL enhances synthesis of TGF-β₁, as evidenced by preliminary work performed on benign prostate cells"<-More synthesis of TGF-Beta1 is great for LSJL as TGF-Beta1 is a great way to induce chondrogenic differentiation.

"Melatonin has a putative[valid] role in collagen synthesis in human bone cells in vitro. Furthermore, it has been suggested that it plays an important part in the stimulation of synthesis of ECM and related molecules, including TGF-β₁, tenascin and fibronectin and also in regulation of ECM construction."<-Melatonin does lots of good stuff that encourages Chondrogenesis.  High levels of Melatonin would seem to increase efficacy of LSJL.  How to raise Melatonin levels though while bypassing the negative feedback loop?

Melatonin enhances cartilage matrix synthesis by porcine articular chondrocytes. 

"The effect of melatonin on cartilage matrix synthesis of articular chondrocytes was evaluated in vitro in a pellet culture system. Melatonin treatment yielded chondrocyte-pellets with a higher expression of chondrogenic markers consisting of collagen II, Sox 9, and aggrecan[so melatonin increases freshly differentiated MSC chondrocyte cell quality] at both the mRNA and protein levels. A hypertrophic marker, collagen X, remained low. up-regulation of internal transforming growth factor beta1 (TGF-beta1) expression was observed in the melatonin-treated cells. "

"Introducing high amounts of TGF-β into a knee joint has adverse effects in the form of marked synovial hyperplasia and chondro-osteophyte formation[chondro-osteophyte is a bone cell within the cartilage, this is good for cartilage within the bone which is what we're trying to induce with LSJL]"<-This is interesting. Hyperplasia equals bigger which is good for the bone and for height.

Sox9 has an impact on chondrogenesis which affects height. So upregulation of Sox9 by melatonin is very good.

Here's some information on the development of Melatonin resistance:

Loss of response to melatonin treatment is associated with slow melatonin metabolism.

"The initial good response to melatonin disappeared within a few weeks after starting treatment, while the good response returned only after considerable dose reduction. We hypothesise that this loss of response is associated with slow melatonin metabolism.

In this study, we determined melatonin clearance in two female (aged 61 and 6 years) and one male (aged 3 years) patients who had chronic insomnia, late melatonin onset and mild ID, and whose sleep quality worsened a few weeks after initial good response to melatonin treatment, suggesting melatonin tolerance. After a 3-week washout period, patients received melatonin 1.0, 0.5 or 0.1 mg, respectively. Salivary melatonin level was measured just before melatonin administration, and 2 and 4 h thereafter. After this melatonin clearance test, melatonin treatment was resumed with a considerably lower dose.

In all patients melatonin concentrations remained >50 pg/mL at 2 and 4 h after melatonin administration. After resuming melatonin treatment sleep problems disappeared. The same procedure was followed in three patients who did not show loss of response to melatonin after 6 months of treatment. In all patients in the control group melatonin concentrations decreased between 2 and 4 h after melatonin administration with a mean of 83%.

Loss of response to melatonin treatment can be caused by slow metabolisation of exogenous melatonin. As melatonin is metabolised in the liver almost exclusively by cytochrome P450 enzyme CYP1A2, this slow melatonin metabolism is probably due to decreased activity/inducibility of CYP1A2[Altering the CYP1A2 enzyme may be a way to increase the response to exogenous melatonin, cycling off Melatonin is the easiest way to increase the CYP1A2 enyzme excitability]. In patients with loss of response to melatonin, a melatonin clearance test should be considered and a considerably dose reduction is advised."

"Melatonin levels in three of the four patients, who received melatonin, were extremely high (>50 pg/mL) after 4 weeks of treatment, while they were very low at baseline."<-Exogenous Melatonin is effective at increasing serum Melatonin levels.

"For CYP1A2, metabolism of most substrates can be described using the Michaelis-Menten equation, demonstrating saturation kinetics. For some substrates in higher concentration the model seems inadequate, suggestive of a two binding sites model, either inhibitory or cooperative. Saturation will fortify the effects of exogenous melatonin in poor metabolisers. Poor metabolisers will initially experience disproportional long lasting higher serum levels after normal doses resulting in effective therapy. During the first stage of saturation they will experience disproportional increase in serum levels after a normal dose, thus still resulting in effective therapy. Finally such a high level will be reached that a next dose will not result in an effective increase of serum level. This could be the explanation for delayed onset of these effects and the huge impact of dosage reduction. The delay in the loss of response to melatonin treatment and the effectiveness of dose reduction with restoration of rhythmicity can be attributed to the saturation phenomenon, with eventually much extended elimination half-life values for melatonin. The proportion of individuals with the slow phenotype narrowly ranges from 12% to 14%[Not an insignificant percentage]"

Another study that shows that exogenous melatonin influences serum melatonin levels:

Endogenous melatonin levels and the fate of exogenous melatonin: age effects.

"This study examines the range of serum melatonin concentrations that occur among young and older adults, and tests the effects of orally administered melatonin on the serum and saliva concentrations of the hormone. Healthy volunteers (20-36 per study), aged 20-73 years, were divided into two groups on the basis of age (29.2 +/- 6.5 and 60 +/- 8.8 years). For study 1: Serum melatonin levels were measured at 15 to 60 min intervals over a 25 h period using a radioimmunoassay. For study 2: serum and saliva melatonin levels were measured before and at intervals after the administration of a 0.3 mg dose of melatonin at 11.00 h[Only 0.3 mg of melatonin was used which is much less than the typical 3 mg used in Melatonin supplements]. The younger subjects had significantly higher peak endogenous melatonin concentrations (+/- SD) and greater inter-individual variability (100.9 +/- 48.6 pg/ml) than the older subjects (34.5 +/- 15.4 pg/ml). Mean melatonin levels following treatment with the hormone tended to be higher and were significantly more variable among the group of older volunteers (254.5 +/- 145.7) than among the younger group (170.2 +/- 22.0 pg/ml)[Older volunteers have higher peak melatonin serum levels, maybe it has to do with the temporarily elevated levels induced by poor Cyp1A2 metabolism]. We conclude that although the peak endogenous serum melatonin levels are lower in elderly adults, the increment in serum melatonin levels induced by a low oral dose of the hormone is greater and more variable among people over 48 years old."

In the young volunteers exogenous Melatonin increased serum levels of Melatonin by 70%. That is quite dramatic.

Melatonin appears to be a good stimulant with possible height increase implications due to its possible enhancement of LSJL induced chondrogenesis and is available for sale:Source Naturals Melatonin 2.5mg, Peppermint, 240 Tablets. 2.5mg of Melatonin may still be too high so here's 1mg: Melatonin 1 mg 120 Caps.  To avoid negative feedback it may be best to take exogenous melatonin intermittently. Or, take a lower mg dosage of Melatonin for a period.

The scavenging properties of Melatonin may be anti-chondrogenic.

Cytoprotective and anti-inflammatory effects of melatonin in hydrogen peroxide-stimulated CHON-001 human chondrocyte cell line and rabbit model of osteoarthritis via the SIRT1 pathway.

"This study examined the effects and underlying mechanism of melatonin in hydrogen peroxide (H(2) O(2) )-stimulated human chondrocytes and rabbit osteoarthritis (OA) model. Melatonin markedly inhibited hydrogen peroxide (H(2) O(2) )-stimulated cytotoxicity, iNOS, and COX-2 protein and mRNA expression, as well as the downstream products, NO and PGE(2)[Both NO and PGE2 may be good for height growth]. Incubation of cells with melatonin decreased H(2) O(2) -induced Sirtuin 1 (SIRT1) mRNA and protein expression. SIRT1 inhibition by sirtinol or Sirt1 siRNA reversed the effects of melatonin on H(2) O(2) -mediated induction of pro-inflammatory cytokines (NO, PGE(2) , TNF-α, IL-1β, and IL-8) and the expression of iNOS, COX-2, and cartilage destruction molecules. Melatonin blocked H(2) O(2) -induced phosphorylation of PI3K/Akt, p38, ERK, JNK, and MAPK, as well as activation of NF-κB[all of these are potentially height increasing proteins and I believe Kinases are activated by being phosphorylated], which was reversed by sirtinol and SIRT1 siRNA."

Geographical distribution of adolescent body height with respect to effective day length in Japan: an ecological analysis.

"The height of Japanese youth raised in the northern region tends to be greater than that of youth raised in the southern region; therefore, a geographical gradient in youth body height exists. This gradient has existed for about 100 years. Consideration of the nutritional improvement, economic growth, and intense migration that has occurred in this period indicates that it is probably the result of environmental rather than nutritional or genetic factors. To identify possible environmental factors, ecological analysis of prefecture-level data on the body size of 8- to 17-year-old youth averaged over a 13-year period (1996 to 2008) and Japanese mesh climatic data on the climatic variables of temperature, solar radiation, and effective day length (duration of photoperiod exceeding the threshold of light intensity) was performed. The geographical distribution of the standardized height of Japanese adolescents was found to be inversely correlated to a great extent with the distribution of effective day length at a light intensity greater than 4000 lx. The results of multiple regression analysis of effective day length, temperature, and weight (as an index of food intake) indicated that a combination of effective day length and weight was statistically significant as predictors of height in early adolescence; however, only effective day length was statistically significant as a predictor of height in late adolescence. Day length may affect height by affecting the secretion of melatonin, a hormone that inhibits sexual and skeletal maturation, which in turn induces increases in height. By affecting melatonin production, regional differences in the duration of the photoperiod may lead to regional differences in height. Exposure to light intensity greater than 4000 lx appears to be the threshold at which light intensity begins to affect the melatonin secretion of humans who spend much of their time indoors."

"[There's a] negative geographical correlation between height and average temperature"

"humans raised in colder climates tend to have larger body sizes than those raised in warmer climates"

Annual mean temperature and annual sun radiation together tended to decrease height.

" Effective day length at 4000 lx was found to be significantly and inversely correlated to a greater extent with height in both sexes, and particularly for 13-year-old males and 12-year-old females"

"Height is negatively correlated to a greater extent with annual mean solar radiation and effective day length than with temperature"

"to delay menses and sexual maturation relatively strong light intensity is required, the distribution of which is strongest between 25–30 degrees of latitude; the light intensity is required in the high latitudes because of lower sun elevation and high cloud cover, and less light intensity is required near the equator because of high cloud cover. These distributions can be explained using the concept of the effective day length, because the distribution of effective day length at a light intensity of more than 1000 lx is almost proportional to the distribution of the amount of solar radiation"

" a light intensity of 50 to 600 lx can induce considerable phase shifts in the human melatonin–circadian rhythm and that phototherapy for treating sleep–wake rhythm disorders is only effective at a light intensity greater than 1000 lx, indicating that a light intensity of 4000 lx is too strong to affect the secretion of melatonin. However, when the modern human lifestyle is taken into consideration–one in which a considerable amount of time is spent indoors–an outdoor light intensity of 4000 lx appears to be an appropriate threshold at which light intensity could begin to affect the melatonin secretion of humans who spend most of their time indoors. In fact, seasonal changes in day length induce seasonal variation in melatonin secretion and physiological changes in the duration of sleep, so that our waking time is earlier in summer and later in winter. This phenomenon is caused by relatively strong daylight that is bright enough to wake individuals who spend most of their time indoors."

Dietary intake, growth and development of children with ADHD in a randomized clinical trial of Ritalin and Melatonin co-administration: Through circadian cycle modification or appetite enhancement?

"It is postulated that ritalin may adversely affect sleep, appetite, weight and growth of some children with ADHD. Therefore, we aimed to evaluate melatonin supplementation effects on dietary intake, growth and development of children with ADHD treated with ritalin through circadian cycle modification and appetite mechanisms.

After obtaining consent from parents, 50 children aged 7-12 with combined form of AD/HD were randomly divided into two groups based on gender blocks: one received melatonin (3 or 6 mg based on weight) combined with ritalin (1mg/kg) and the other took placebo combined with ritalin (1mg/kg) in a double blind randomized clinical trial. Three-day food record, and standard weight and height of children were evaluated prior to the treatment and 8 weeks after the treatment. Children's appetite and sleep were evaluated in weeks 0, 2, 4 and 8.

Paired sample t-test showed significant changes in sleep latency (23.15±15.25 vs. 17.96±11.66) and total sleep disturbance score (48.84±13.42 vs. 41.30±9.67) before and after melatonin administration, respectively. However, appetite and food intake did not change significantly during the study. Sleep duration and appetite were significantly correlated in melatonin group (Pearson r=0.971). Mean height (138.28±16.24 vs. 141.35±16.78) and weight (36.73±17.82 vs. 38.97±17.93) were significantly increased in melatonin treated children before and after the trial.

Administration of melatonin along with ritalin improves height and weight growth of children. These effects may be attributed to circadian cycle modification, increasing sleep duration and the consequent more growth hormone release during sleep."

So is the increased height due to food consumption or due additional affects of the Melatonin.

"Melatonin stimulates growth hormone release as well as growth hormone responsiveness to growth hormone-releasing hormone (GHRH) secretion."

Abnormal Skeletal Growth in Adolescent Idiopathic Scoliosis Is Associated with Abnormal Quantitative Expression of Melatonin Receptor, MT2.

"melatonin receptor, MT2, was undetectable in some AIS girls. The present study aimed to investigate whether the abnormal MT2 expression in AIS is quantitative or qualitative. Cultured osteoblasts were obtained from 41 AIS girls and nine normal controls. Semi-quantification of protein expression by Western blot and mRNA expression by TaqMan real-time PCR for both MT1 and MT2 were performed. Anthropometric parameters were also compared and correlated with the protein expression and mRNA expression of the receptors. The results showed significantly lower protein and mRNA expression of MT2 in AIS girls compared with that in normal controls (p = 0.02 and p = 0.019, respectively). No differences were found in the expression of MT1. When dichotomizing the AIS girls according to their MT2 expression, the group with low expression was found to have a significantly longer arm span. The results of this study showed for the first time a quantitative change of MT2 in AIS that was also correlated with abnormal arm span as part of abnormal systemic skeletal growth."

"The activation of MT1 or MT2 by melatonin can inhibit adenylate cyclase activity, resulting in the inhibition of forskolin-induced cyclic AMP formation and leads to a decrease in activated protein kinase A and subsequent downstream signaling."

Melatonin enhances chondrogenic differentiation of human mesenchymal stem cells

"the effects of melatonin on human mesenchymal stem cells (MSCs) undergoing chondrogenic differentiation were investigated. Cells were induced along chondrogenic differentiation via high density micromass culture in chondrogenic medium containing vehicle or 50 nM melatonin. Histological study and quantitative analysis of glycosaminoglycan (GAG) showed induced-cartilage tissues to be larger and richer in GAG, collagen type II, and collagen type X in the melatonin group than in the untreated controls. Real time RT-PCR analysis demonstrated that melatonin treatment significantly up-regulated the expression of the genes involved in chondrogenic differentiation, including aggrecan (ACAN), collagen type II (COL2A1), collagen type X (COL10A1), SRY (sex determining region Y)-box 9 (SOX9), runt-related transcription factor 2 (RUNX2), and the potent inducer of chondrogenic differentiation, bone morphogenetic protein 2 (BMP2). And the expression of melatonin membrane receptors (MT) MT1 and MT2 were detected in the chondrogenic-induced-MSCs by immunofluorescence staining. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to increase the size and GAG synthesis of the induced-cartilage tissues, as well as to completely reverse the effect of melatonin on the gene expression of ACAN, COL2A1, COL10A1, SOX9 and BMP2 after 7 days of differentiation. These findings demonstrate that melatonin enhances chondrogenic differentiation of human MSCs at least partially through melatonin receptors."

"phosphorylation of smad1/5/8 is positively involved in cartilage development"

So MT1 and MT2 enhance chondrogenesis.