This is one of the most commonly asked questions for people who want to exercise to increase their height in a more natural way. So…”what is the best exercise for height increase and to grow taller?”

Answer: Stretching and Yoga, which I wanted to include the two as one main thing. In the physical aspect of yoga, you are expected to position your body in postures known as asanas so you can manipulate the body to give it the amount of flexibility, durability, and strength to handle the very intense meditative practices of the mind. The original purpose of yoga was always to rediscover the union with “god” again as stated in the ancient vedas and yogis of India. There are dozens if not hundreds of yogic branches and teachings with many qualified teachers. While some yogas like jhana and raja are more about the mind and mind exercises, many other type sof yogas expect the practitioner to push their bodies to their limits. This means a lot of contortioning and stretching of the body’s limbs and joints to become more nimble. The stretching thus leads to more flexibility. The joints are often stretched out more from tensile pulling.

Over time, the stretching causes the body to be more relaxed and the muscles to be less tense. The less tightening of the muscles means the human back and vertebrate can thus open up and expand more than they usually are. From this type of stretching, the height of the individual can increase a little more.

We know that the human growth hormones start from the pituitary gland in the front side area. Let’s do a little more analysis and research on the gland itself.

From Wikipedia HERE …

In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 grams (0.018 oz) in humans. It is not a part of the brain. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity (sella turcica) covered by a duralfold (diaphragma sellae). The pituitary is functionally connected to the hypothalamus by the median eminence via a small tube called the infundibular stem (Pituitary stalk). The pituitary fossa, in which the pituitary gland sits, is situated in the sphenoid bone in the middle cranial fossa at the base of the brain. The pituitary gland secretes nine hormones that regulate homeostasis.

Sections

The pituitary gland consists of two components: the anterior pituitary (or adenohypophysis) and the posterior pituitary (or neurohypophysis), and is functionally linked to the hypothalamus by the pituitary stalk (also named the “infundibular stem”, or simply the “infundibulum”). It is from the hypothalamus that hypothalamic tropic factors are released to descend down the pituitary stalk to the pituitary gland where they stimulate the release of pituitary hormones. While the pituitary gland is known as the ‘master’ endocrine gland, both of the lobes are under the control of the hypothalamus; the anterior pituitary receives its signals from the parvocellular neurons and the posterior pituitary receives its signals from magnocellular neurons.

Anterior pituitary (Adenohypophysis)

The anterior pituitary synthesizes and secretes the following important endocrine hormones:

Somatotrophins:

• Growth hormone (also referred to as ‘Human Growth Hormone’, ‘HGH’ or ‘GH’ or somatotropin), released under influence of hypothalamic Growth Hormone-Releasing Hormone (GHRH); inhibited by hypothalamic Somatostatin

Thyrotrophins:

• Thyroid-stimulating hormone (TSH), released under influence of hypothalamic Thyrotropin-Releasing Hormone (TRH)

Corticotropins:

• Adrenocorticotropic hormone (ACTH), released under influence of hypothalamic Corticotropin-Releasing Hormone (CRH)
• Beta-endorphin, released under influence of hypothalamic Corticotropin-Releasing Hormone (CRH)^[3]

Lactotrophins:

• Prolactin (PRL), also known as ‘Luteotropic’ hormone (LTH), whose release is inconsistently stimulated by hypothalamic TRH, oxytocin, vasopressin, vasoactive intestinal peptide, angiotensin II, neuropeptide Y, galanin, substance P, bombesin-like peptides (gastrin-releasing peptide, neuromedin B and C), and neurotensin, and inhibited by hypothalamic dopamine.^[4]

Gonadotropins:

• Luteinizing hormone (also referred to as ‘Lutropin’ or ‘LH’ or, in males, ‘Interstitial Cell-Stimulating Hormone’ (ICSH))
• Follicle-stimulating hormone (FSH), both released under influence of Gonadotropin-Releasing Hormone (GnRH)

Melanotrophins

• Melanocyte–stimulating hormones (MSHs) or “intermedins,” as these are released by the pars intermedia, which is “the middle part”; adjacent to the posterior pituitary lobe, pars intermedia is a specific part developed from the anterior pituitary lobe.

These hormones are released from the anterior pituitary under the influence of the hypothalamus. Hypothalamic hormones are secreted to the anterior lobe by way of a special capillary system, called thehypothalamic-hypophysial portal system.

The anterior pituitary is divided into anatomical regions known as the pars tuberalis, pars intermedia, and pars distalis. It develops from a depression in the dorsal wall of the pharynx (stomodial part) known as Rathke’s pouch.

Posterior pituitary (Neurohypophysis)

The posterior pituitary stores and secretes the following important endocrine hormones:

Magnocellular Neurons:

• Oxytocin, most of which is released from the paraventricular nucleus in the hypothalamus
• Antidiuretic hormone (ADH, also known as vasopressin and AVP, arginine vasopressin), the majority of which is released from the supraoptic nucleus in the hypothalamus

Oxytocin is one of the few hormones to create a positive feedback loop. For example, uterine contractions stimulate the release of oxytocin from the posterior pituitary, which, in turn, increases uterine contractions. This positive feedback loop continues throughout labor.

Intermediate lobe

Although rudimentary in humans (and often considered part of the anterior pituitary), the intermediate lobe located between the anterior and posterior pituitary is important to many animals. For instance, in fish, it is believed to control physiological color change. In adult humans, it is just a thin layer of cells between the anterior and posterior pituitary. The intermediate lobe produces melanocyte-stimulating hormone(MSH), although this function is often (imprecisely) attributed to the anterior pituitary.

Variations among vertebrates

The pituitary gland is found in all vertebrates, but its structure varies between different groups.

The division of the pituitary described above is typical of mammals, and is also true, to varying degrees, of all tetrapods. However, only in mammals does the posterior pituitary have a compact shape. Inlungfishes, it is a relatively flat sheet of tissue lying above the anterior pituitary, and, in amphibians, reptiles, and birds, it becomes increasingly well developed. The intermediate lobe is, in general, not well developed in tetrapods, and is entirely absent in birds.^[5]

Apart from lungfishes, the structure of the pituitary in fish is generally different from that in tetrapods. In general, the intermediate lobe tends to be well developed, and may equal the remainder of the anterior pituitary in size. The posterior lobe typically forms a sheet of tissue at the base of the pituitary stalk, and in most cases sends irregular finger-like projection into the tissue of the anterior pituitary, which lies directly beneath it. The anterior pituitary is typically divided into two regions, a more anterior rostral portion and a posterior proximal portion, but the boundary between the two is often not clearly marked. Inelasmobranchs there is an additional, ventral lobe beneath the anterior pituitary proper.^[5]

The arrangement in lampreys, which are among the most primitive of all fish, may indicate how the pituitary originally evolved in ancestral vertebrates. Here, the posterior pituitary is a simple flat sheet of tissue at the base of the brain, and there is no pituitary stalk. Rathke’s pouch remains open to the outside, close to the nasal openings. Closely associated with the pouch are three distinct clusters of glandular tissue, corresponding to the intermediate lobe, and the rostral and proximal portions of the anterior pituitary. These various parts are separated by meningial membranes, suggesting that the pituitary of other vertebrates may have formed from the fusion of a pair of separate, but associated, glands.^[5]

Most armadillo also possess a urophysis, a neural secretory gland very similar in form to the posterior pituitary, but located in the tail and associated with the spinal cord. This may have a function inosmoregulation.^[5]

There is an analogous structure in the octopus brain.^[6

From the Department Of Neurological Surgery at the University of Pittburgh website HERE…

From the website Cancer.Net HERE ….

About the pituitary gland

The pituitary gland is a small gland located near the brain. This gland is often referred to as the “master endocrine gland” because it releases hormones that affect many bodily functions. The pituitary gland is controlled by the hypothalamus, a small structure also near the brain that is connected to the pituitary gland. A pituitary gland has two lobes, the anterior (front) and the posterior (back), and each lobe is responsible for releasing specific hormones. These different hormones include:

Anterior pituitary lobe hormones

• Thyroid stimulating hormone (TSH) stimulates the thyroid gland, which helps regulate the body’s metabolism
• Adrenocorticotrophic hormone (ACTH) controls the hormones released by the adrenal gland that support blood pressure, metabolism, and the body’s response to stress
• Gonadotropins (Follicle stimulating hormone or FSH and Luteinizing hormone or LH) stimulate production of sperm in a man’s testicles or eggs in a woman’s ovaries and regulate a woman’s menstrual cycle
• Growth hormone promotes growth of the long bones in the arms and legs, thickens the skull and bones of the spine, and causes the tissue over the bones to thicken
• Prolactin stimulates milk production in women after childbirth
• Lipotropin stimulates the movement of fat from the body to the bloodstream
• Melanocyte stimulating hormone (MSH) regulates the production of melanin, the pigment in skin

Posterior pituitary lobe hormones

• Oxytocin stimulates contraction of the uterus during childbirth and the flow of milk during breastfeeding
• Antidiuretic hormone (called vasopressin) increases reabsorption of water by the kidneys and allows a person to stay hydrated

Tumors in the pituitary gland

When normal cells change and grow uncontrollably, they can form a mass called a tumor. A pituitary gland tumor can be benign (noncancerous and located only in the pituitary gland) or malignant (cancerous, meaning it can spread to other parts of the body). Most often, pituitary gland tumors are noncancerous growths and are called pituitary adenomas. However, a pituitary gland tumor can occasionally act like a cancerous tumor by growing into nearby tissue and structures, or rarely, spreading to other parts of the body.

Pituitary gland tumors are NOT brain tumors, as the pituitary gland is located under and is separate from the brain. However, a tumor in this gland can be very serious because a pituitary gland that doesn’t work can cause problems with other organs. The tumor can also press on nearby structures, such as the optic nerves, impairing a person’s sight.

Me: The big thing for us height seekers to note is that the Pituitary gland is not actually a part of the brain but actually the lower part of the hypothalamus and is connected by a small tube called the infundibular stem (Pituitary stalk). It releases 9 major hormones that regulate the body’s homeostasis. There is two parts to it although the truth is that the gland is actually a combination of different functioning cells. The HGH is just one of the 9 hormones being released. The hormone release is regulated by the either the growth hormone releasing hormone (GHRH) or the growth hormone inhibiting hormone (GHIH) which is released by the hypothalamus. Hypothalamic hormones are secreted to the anterior lobe by way of a special capillary system, called thehypothalamic-hypophysial portal system. The pituitary giants we get are usually from the clumping of certain cells in the pituitary coming together which is usually benign.

The Insulin like Growth Factor (IGF-1) is another one of those pieces in the human growth mechanism that we have to learn and understand for us to build a better knowledge base to work from.

Of course I always try to answer the most obvious question, “What is Insulin like Growth Factor (IGF-1)?”

This time I am just going to copy and paste the entire Wikipedia article below and highlight the important parts (source HERE).  This piece of the puzzle is just as critical to learn as the GH.

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a “sulfation factor”and its effects were termed “nonsuppressible insulin-like activity” (NSILA) in the 1970s.

IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. A synthetic analog of IGF-1, mecasermin is used for the treatment of growth failure.

IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 17,066 daltons.

IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by growth hormone (GH) and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5B. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio.

Synthesis and circulation

In rat experiments the amount of IGF-1 mRNA in the liver was positively associated with dietary casein and negatively associated with a protein-free diet.

Recently, an efficient plant expression system was developed to produce biologically active recombinant human IGF-I (rhIGF-I) in transgenic rice grains.

Mechanism of action

Its primary action is mediated by binding to its specific receptor, the Insulin-like growth factor 1 receptor, abbreviated as “”IGF1R””, present on many cell types in many tissues. Binding to the IGF1R, a receptor tyrosine kinase, initiates intracellular signaling; IGF-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death.

IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerves, skin, hematopoietic cell, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis.

Deficiency of either growth hormone or IGF-1 therefore results in diminished stature. GH-deficient children are given recombinant GH to increase their size. IGF-1 deficient humans, who are categorized as having Laron syndrome, or Laron’s dwarfism, are treated with recombinant IGF-1. In beef cattle, circulating IGF-I concentrations are related to reproductive performance.

Insulin-like growth factor 1 receptor (IGF-1R) and other tyrosine kinase growth factor receptors signal through multiple pathways. A key pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of rapamycin (mTOR). Rapamycins complex with FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by upregulating Akt, driving signals through the inhibited mTORC1. Phosphorylation of eukaryotic initiation factor 4e (eif-4E) [4EBP] by mTOR inhibits the capacity of 4EBP to inhibit eif-4E and slow metabolism.

Receptors

IGF-1 binds to at least two cell surface receptors: the IGF-1 receptor (IGF1R), and the insulin receptor. The IGF-1 receptor seems to be the “physiologic” receptor – it binds IGF-1 at significantly higher affinity than the IGF-1 that is bound to the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase – meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the insulin receptor at approximately 0.1x the potency of insulin. Part of this signaling may be via IGF1R/Insulin Receptor heterodimers (the reason for the confusion is that binding studies show that IGF1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF1 in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia)..

IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.

Other IGFBPs are inhibitory. For example, both IGFBP-2 and IGFBP-5 bind IGF-1 at a higher affinity than it binds its receptor. Therefore, increases in serum levels of these two IGFBPs result in a decrease in IGF-1 activity.

Related growth factors

IGF-1 is closely related to a second protein called “IGF-2”. IGF-2 also binds the IGF-1 receptor. However, IGF-2 alone binds a receptor called the “IGF-2 receptor” (also called the mannose-6 phosphate receptor). The insulin growth factor-II receptor (IGF2R) lacks signal transduction capacity, and its main role is to act as a sink for IGF-2 and make less IGF-2 available for binding with IGF-1R. As the name “insulin-like growth factor 1” implies, IGF-1 is structurally related to insulin, and is even capable of binding the insulin receptor, albeit at lower affinity than insulin.

A splice variant of IGF-1 sharing an identical mature region, but with a different E domain is known as mechano growth factor (MGF).

Contribution to ageing

It is now widely accepted that signaling through the insulin/IGF-1-like receptor pathway is a significant contributor to the biological aging process in many organisms. This avenue of research first achieved prominence with the work of Cynthia Kenyon, who showed that mutations in the daf-2 gene could double the lifespan of the roundworm C. elegans. daf-2 encodes the worm’s unified insulin/IGF-1-like receptor.

Insulin/IGF-1-like signaling is conserved from worms to humans. In vitro experiments show that mutations that reduce insulin/IGF-1 signaling have been shown to decelerate the degenerative aging process and extend lifespan in a wide range of organisms, including Drosophila melanogaster, mice, and possibly humans. Reduced IGF-1 signaling is also thought to contribute to the “anti-aging” effects of Calorie restriction.

Nevertheless the situation in vivo is evidently different, Anabolic deficiency in men with chronic heart failure is prevalent and could have an associated detrimental impact on survival. Deficiency of anabolic hormones identifies groups with a higher mortality.

Factors influencing the levels in the circulation

Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake. The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals – see also endocrine disruptor.

Neuropathy

Therapeutic administration with neurotrophic proteins (IGF I) is associated with potential reversal of degeneration of spinal cord motor neuron axons in certain peripheral neuropathies.

Dwarfism

Rare diseases characterized by inability to make or respond to IGF-1 produce a distinctive type of growth failure. One such disorder, termed Laron dwarfism does not respond at all to growth hormone treatment due to a lack of GH receptors. The FDA has grouped these diseases into a disorder called severe primary IGF deficiency. Patients with severe primary IGFD typically present with normal to high GH levels, height below -3 standard deviations (SD), and IGF-1 levels below -3SD. Severe primary IGFD includes patients with mutations in the GH receptor, post-receptor mutations or IGF mutations, as previously described. As a result, these patients cannot be expected to respond to GH treatment.

People with Laron syndrome have strikingly low rates of cancer and [diabetes].

IGF-I and Cancer

The IGF signaling pathway has a pathogenic role in cancer. Studies have shown that increased levels of IGF lead to increased growth of existing cancer cells. People with Laron syndrome have also recently been shown to be of much less risk to develop cancer.

Use as a diagnostic test

Interpretation of IGF-1 levels is complicated by the wide normal ranges, and variations by age, sex, and pubertal stage. Clinically significant conditions and changes may be masked by the wide normal ranges. Sequential management over time is often useful for the management of several types of pituitary disease, undernutrition, and growth problems.IGF-1 levels can be measured in the blood in 10-1000 ng/ml amounts. As levels do not fluctuate greatly throughout the day for an individual person, IGF-1 is used by physicians as a screening test for growth hormone deficiency and excess in acromegaly and gigantism.

As a therapeutic agent

Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure. IGF-1 has been manufactured recombinantly on a large scale using both yeast and E. coli.

Several companies have evaluated IGF-1 in clinical trials for a variety of additional indications, including type 1 diabetes, type 2 diabetes, amyotrophic lateral sclerosis(ALS aka “Lou Gehrig’s Disease”), severe burn injury and myotonic muscular dystrophy (MMD). Results of clinical trials evaluating the efficacy of IGF-1 in type 1 diabetes and type 2 diabetes showed great promise in reducing hemoglobin A1C levels, as well as daily insulin consumption. However, the sponsor, Genentech, discontinued the program due to an exacerbation of diabetic retinopathy in patients coupled with a shift in corporate focus towards oncology. Cephalon and Chiron conducted two pivotal clinical studies of IGF-1 for ALS, and although one study demonstrated efficacy, the second was equivocal, and the product has never been approved by the FDA.

However, in the last few years, two additional companies Tercica and Insmed compiled enough clinical trial data to seek FDA approval in the United States. In August 2005, the FDA approved Tercica’s IGF-1 drug, Increlex, as replacement therapy for severe primary IGF-1 deficiency based on clinical trial data from 71 patients. In December 2005, the FDA also approved Iplex, Insmed’s IGF-1/IGFBP-3 complex. The Insmed drug is injected once a day versus the twice-a-day version that Tercica sells.

Insmed was found to infringe on patents licensed by Tercica, which then sought to get a U.S. district court judge to ban sales of Iplex.^[26] To settle patent infringement charges and resolve all litigation between the two companies, Insmed in March 2007 agreed to withdraw Iplex from the U.S. market, leaving Tercica’s Increlex as the sole version of IGF-1 available in the United States.

By delivering Iplex in a complex, patients might get the same efficacy with regard to growth rates but experience fewer side effects with less severe hypoglycemia. This medication might emulate IGF-1’s endogenous complexing, as in the human body 97–99% of IGF-1 is bound to one of six IGF binding proteins. IGFBP-3 is the most abundant of these binding proteins, accounting for approximately 80% of IGF-1 binding.

In a clinical trial of an investigational compound MK-677, which raises IGF-1 in patients, did not result in an improvement in patients’ Alzheimer’s symptoms. Another clinical demonstrated that Cephalon’s IGF-1 does not slow the progression of weakness in ALS patients, but other studies shown strong beneficial effects of IGF-I replacement therapy in ALS patients, and therefore IGF-I may have the potential to be an effective and safe medicine against ALS, however other studies had conflicting results.

IGFBP-3 is a carrier for IGF-1, meaning that IGF-1 binds IGFBP-3, creating a complex whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life in serum. Without binding to IGFBP-3, IGF-1 is cleared rapidly through the kidney, due to its low molecular weight. But when bound to IGFBP-3, IGF-1 evades renal clearance. Also, since IGFBP-3 has a lower affinity for IGF-1 than IGF-1 has for its receptor, IGFR, its binding does not interfere with IGF-1 function. For these reasons, an IGF-1/IGFBP-3 combination approach was approved for human treatment… brought forward by a small company called Insmed. However, Insmed fell afoul patent issues, and was ordered to desist in this approach.

IGF-1 has also been shown to be effective in animal models of stroke when combined with Erythropoietin. Both behavioural and cellular improvements were found.

Interactions

Insulin-like growth factor 1 has been shown to bind and interact with all the IGF-1 Binding Proteins (IGFBPs), of which there are six (IGFBP1-6).

Specific references are provided for interactions with IGFBP3, IGFBP4, and IGFBP7.

Me: What the main takeaways from the wikipedia article are is that the IGF-1 is that IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerves, skin, hematopoietic cell, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis. deficiency of IGF-1 receptors is Laron Syndrome. The IGF-1 is very similar to insulin but only binds to insulin receptors at 1/10th the rate of the IGF-1 receptors. The IGF-1 receptors is tyrosine kinase activated, which tursn on the AKT signaling pathway. What is shown in others studies is that the IGF-1 signaling pathway also is a significant contributor to the aging process and well as increased levels of cancer. There are ways to produce synthetic IGF using yeast and E-coli and the IGF are processed and can be used only a a very specific group of people who suffer from IGF-1 deficiency. 

In the broader scheme of things this could be mean for some people that there is a strong correlation between height and aging and cancer. People who may be genetically prone to tallness may be prone to age faster than their shorter counterparts and be more likely to develop cancer.

This is the second article in a series of posts where I study and understand the major components that are part of the human height growth process. You should read and follow along so you will be able to get a better understanding of what I am talking about in future posts. The facts are that the technicality of future posts will only get more and more scientific.

The element I wanted to study and analyze in this post is the Human Growth Hormone, HGH. The first question is “What is human growth hormone?”

For the easiest quickest definition, we go to Wikipedia (source HERE)…

Growth hormone (GH) is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland. Somatotropin (STH) refers to the growth hormone 1 produced naturally in animals, whereas the term somatropin refers to growth hormone produced by recombinant DNA technology, and is abbreviated “HGH” in humans.

Me: It is a 191 amino acid single chain polypeptide. It is created, stored, and released by the Somatotropic (Def: have a stimulating effect on body growth) cells on the side of the front of the pituitary gland. The stuff created synthetically in the lab is called somatropin.

Growth hormone is used as a prescription drug in medicine to treat children’s growth disorders and adult growth hormone deficiency. In the United States, it is only available legally from pharmacies, by prescription from a doctor. In recent years in the United States, some doctors have started to prescribe growth hormone in GH-deficient older patients (but not on healthy people) to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. At this time, HGH is still considered a very complex hormone, and many of its functions are still unknown.

In its role as an anabolic agent, HGH has been abused by competitors in sports since the 1970s, and it has been banned by the IOC and NCAA. Traditional urine analysis could not detect doping with HGH, so the ban was unenforceable until the early 2000s when blood tests that could distinguish between natural and artificial HGH were starting to be developed. Blood tests conducted by WADA at the 2004 Olympic Games in Athens, Greece targeted primarily HGH. This use for the drug is not approved by the FDA.

Me: The GH can be used for more than just height increase application, but also used to increase vitality, muscle mass gain, energy, and possibly even reverse or hold off aging. For some people, this type of steroidal use represents almost is like the holy grail for bodybuilders and longevity researchers.

From the same Wikipedia article on Growth Hormones… (As always, the most important parts are highlighted)

Biology

Gene locus

Genes for human growth hormone, known as growth hormone 1 (somatotropin) and growth hormone 2, are localized in the q22-24 region of chromosome 17^[3][4] and are closely related to human chorionic somatomammotropin (also known as placental lactogen) genes. GH, human chorionic somatomammotropin, and prolactin belong to a group of homologous hormones with growth-promoting and lactogenic activity.

Structure

The major isoform of the human growth hormone is a protein of 191 amino acids and a molecular weight of 22,124 daltons. The structure includes four helices necessary for functional interaction with the GH receptor. It appears that, in structure, GH is evolutionarily homologous to prolactin and chorionic somatomammotropin. Despite marked structural similarities between growth hormone from different species, only human and Old World monkey growth hormones have significant effects on the human growth hormone receptor.

Several molecular isoforms of GH exist in the pituitary gland and are released to blood. In particular, a variant of approximately 20 kDa originated by an alternative splicing is present in a rather constant 1:9 ratio, while recently an additional variant of ~ 23-24 kDa has also been reported in post-exercise states at higher proportions. This variant has not been identified, but it has been suggested to coincide with a 22 kDa glycosilated variant of 23 kDa identified in the pituitary gland. Furthermore, these variants circulate partially bound to a protein (growth hormone-binding protein, GHBP), which is the truncated part of the growth hormone receptor, and an acid-labile subunit (ALS).

Biological regulation

Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus. These cells release the peptides Growth hormone-releasing hormone (GHRH or somatocrinin) and Growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal venous blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.

Somatotropic cells in the anterior pituitary gland then synthesize and secrete GH in a pulsatile manner, in response to these stimuli by the hypothalamus. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep with plasma levels of 13 to 72 ng/mL. Otherwise there is wide variation between days and individuals. Nearly fifty percent of GH secretion occurs during the third and fourth NREM sleep stages. Surges of secretion during the day occur at 3- to 5-hour intervals. The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL. Between the peaks, basal GH levels are low, usually less than 5 ng/mL for most of the day and night. Additional analysis of the pulsatile profile of GH described in all cases less than 1 ng/ml for basal levels while maximum peaks were situated around 10-20 ng/mL.

A number of factors are known to affect GH secretion, such as age, gender, diet, exercise, stress, and other hormones. Young adolescents secrete GH at the rate of about 700 μg/day, while healthy adults secrete GH at the rate of about 400 μg/day.

Stimulators of growth hormone (GH) secretion include:

• peptide hormones
  • GHRH (somatocrinin) through binding to the growth hormone-releasing hormone receptor (GHRHR)
  • ghrelin through binding to growth hormone secretagogue receptors (GHSR)
• sex hormones
  • increased androgen secretion during puberty (in males from testis and in females from adrenal cortex)
  • estrogen
• clonidine and L-DOPA by stimulating GHRH release
• hypoglycemia, arginine and propranolol by inhibiting somatostatin release
• deep sleep
• niacin as nicotinic acid (Vitamin B3)
• fasting
• vigorous exercise

Inhibitors of GH secretion include:

• GHIH (somatostatin) from the periventricular nucleus
• circulating concentrations of GH and IGF-1 (negative feedback on the pituitary and hypothalamus)
• hyperglycemia
• glucocorticoids
• dihydrotestosterone

In addition to control by endogenous and stimulus processes, a number of foreign compounds (xenobiotics such as drugs and endocrine disruptors) are known to influence GH secretion and function.

Normal functions of GH produced by the body

Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones, GH acts by interacting with a specific receptor on the surface of cells.

Increased height during childhood is the most widely known effect of GH. Height appears to be stimulated by at least two mechanisms:

1. Because polypeptide hormones are not fat-soluble, they cannot penetrate sarcolemma. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway. Through this mechanism GH directly stimulates division and multiplication of chondrocytes ofcartilage.
2. GH also stimulates, through the JAK-STAT signaling pathway, the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it what appears to be both an endocrine and anautocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.

In addition to increasing height in children and adolescents, growth hormone has many other effects on the body:

• Increases calcium retention, and strengthens and increases the mineralization of bone
• Increases muscle mass through sarcomere hyperplasia
• Promotes lipolysis
• Increases protein synthesis
• Stimulates the growth of all internal organs excluding the brain
• Plays a role in homeostasis
• Reduces liver uptake of glucose
• Promotes gluconeogenesis in the liver
• Contributes to the maintenance and function of pancreatic islets
• Stimulates the immune system

Problems caused when the body produces too much GH

The most common disease of GH excess is a pituitary tumor composed of somatotroph cells of the anterior pituitary. These somatotroph adenomas are benign and grow slowly, gradually producing more and more GH. For years, the principal clinical problems are those of GH excess. Eventually, the adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement.

Prolonged GH excess thickens the bones of the jaw, fingers and toes. Resulting heaviness of the jaw and increased size of digits is referred to as acromegaly. Accompanying problems can include sweating, pressure on nerves (e.g., carpal tunnel syndrome), muscle weakness, excess sex hormone-binding globulin (SHBG), insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function.

GH-secreting tumors are typically recognized in the fifth decade of life. It is extremely rare for such a tumor to occur in childhood, but, when it does, the excessive GH can cause excessive growth, traditionally referred to as pituitary gigantism.

Surgical removal is the usual treatment for GH-producing tumors. In some circumstances, focused radiation or a GH antagonist such as pegvisomant may be employed to shrink the tumor or block function. Other drugs like octreotide (somatostatin agonist) and bromocriptine (dopamine agonist) can be used to block GH secretion because both somatostatin and dopamine negatively inhibit GHRH-mediated GH release from the anterior pituitary.^{[citation needed]}

Problems caused when the body produces too little GH

The effects of growth hormone deficiency vary depending on the age at which they occur. In children, growth failure and short stature are the major manifestations of GH deficiency, with common causes including genetic conditions and congenital malformations. It can also cause delayed sexual maturity. In adults, deficiency is rare, with the most common cause a pituitary adenoma, and others including a continuation of a childhood problem, other structural lesions or trauma, and very rarely idiopathic GHD.

Adults with GHD “tend to have a relative increase in fat mass and a relative decrease in muscle mass and, in many instances, decreased energy and quality of life”.

Diagnosis of GH deficiency involves a multiple-step diagnostic process, usually culminating in GH stimulation tests to see if the patient’s pituitary gland will release a pulse of GH when provoked by various stimuli.

HGH in human medicine

FDA-approved treatments with GH related to deficiency of GH

Treatment with exogenous GH is indicated only in limited circumstances, and needs regular monitoring due to the frequency and severity of side-effects. GH is used as replacement therapy in adults with GH deficiency of either childhood-onset (after completing growth phase) or adult-onset (usually as a result of an acquired pituitary tumor). In these patients, benefits have variably included reduced fat mass, increased lean mass, increased bone density, improved lipid profile, reduced cardiovascular risk factors, and improved psychosocial well-being.

FDA-approved treatments with GH unrelated to deficiency of GH

GH can be used to treat conditions that produce short stature but are not related to deficiencies in GH. However, results are not as dramatic when compared to short stature that is solely attributable to deficiency of GH. Examples of other causes of shortness often treated with GH are Turner syndrome, chronic renal failure, Prader–Willi syndrome, intrauterine growth retardation, and severe idiopathic short stature. Higher (“pharmacologic”) doses are required to produce significant acceleration of growth in these conditions, producing blood levels well above normal (“physiologic”). Despite the higher doses, side-effects during treatment are rare, and vary little according to the condition being treated.

One version of rHGH has also been FDA approved for maintaining muscle mass in wasting due to AIDS.

Experimental uses

The following discussion describes experimental uses of GH, that are legal when the GH is prescribed by a doctor. However, the efficacy and safety of use of GH as anti-aging agent are unknown as this use has not been tested in a double-blinded clinical trial.

In recent years in the United States, some doctors have started to prescribe growth hormone in GH-deficient older patients (but not on healthy people) to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. At this time, hGH is still considered a very complex hormone, and many of its functions are still unknown.

Claims for GH as an anti-aging treatment date back to 1990 when the New England Journal of Medicine published a study wherein GH was used to treat 12 men over 60. At the conclusion of the study, all the men showed statistically significant increases in lean body mass and bone mineral density, while the control group did not. The authors of the study noted that these improvements were the opposite of the changes that would normally occur over a 10- to 20-year aging period. Despite the fact the authors at no time claimed that GH had reversed the aging process itself, their results were misinterpreted as indicating that GH is an effective anti-aging agent. This has led to organizations such as the controversial American Academy of Anti-Aging Medicine promoting the use of this hormone as an “anti-aging agent”.

A Stanford University School of Medicine meta-analysis of clinical studies on the subject published in early 2007 showed that the application of GH on healthy elderly patients increased muscle by about 2 kg and decreased body fat by the same amount. However, these were the only positive effects from taking GH. No other critical factors were affected, such as bone density, cholesterol levels, lipid measurements, maximal oxygen consumption, or any other factor that would indicate increased fitness. Researchers also did not discover any gain in muscle strength, which led them to believe that GH merely let the body store more water in the muscles rather than increase muscle growth. This would explain the increase in lean body mass.

GH has also been used experimentally to treat multiple sclerosis, to enhance weight loss in obesity, as well as in fibromyalgia, heart failure, Crohn’s disease and ulcerative colitis, and burns. GH has also been used experimentally in patients with short bowel syndrome to lessen the requirement for intravenous total parenteral nutrition.

Side-effects

Use of GH as a drug has been approved by the FDA for several indications. This means that the drug has acceptable safety in light of its benefits when used in the approved way. Like every drug, there are several side effects caused by GH, some common, some rare. Injection-site reaction is common. More rarely, patients can experience joint swelling, joint pain, carpal tunnel syndrome, and an increased risk of diabetes. In some cases, the patient can produce an immune response against GH. GH may also be a risk factor for Hodgkin’s lymphoma.

One survey of adults that had been treated with replacement cadaver GH (which has not been used anywhere in the world since 1985) during childhood showed a mildly increased incidence of colon cancer and prostate cancer, but linkage with the GH treatment was not established.

Non-medical use in athletic enhancement

Athletes in many sports have used human growth hormone in order to attempt to enhance their athletic performance. Some recent studies have not been able to support claims that human growth hormone can improve the athletic performance of professional male athletes. Many athletic societies ban the use of GH and will issue sanctions against athletes who are caught using it. In the United States, GH is legally available only by prescription from a medical doctor.

Use of GH in production of meat and milk

In the United States, it is legal to give a bovine GH to dairy cows to increase milk production, but it is not legal to use GH in raising cows for beef; see articles on Bovine somatotropin, cattle feeding, dairy farming and the beef hormone controversy.

Use in poultry farming is illegal in the United States as per the poultry farming article.

Several companies have attempted to have a version of GH for use in pigs (porcine somatotropin) approved by the FDA but all applications have been withdrawn.

History of use and manufacture of GH as a drug

The identification, purification and later synthesis of growth hormone is associated with Choh Hao Li. Genentech pioneered the first use of recombinant human growth hormone for human therapy in 1981.

Prior to its production by recombinant DNA technology, growth hormone used to treat deficiencies was extracted from the pituitary glands of cadavers. Attempts to create a wholly synthetic HGH failed. Limited supplies of HGH resulted in the restriction of HGH therapy to the treatment of idiopathic short stature.^[45] Very limited clinical studies of growth hormone derived from an old world monkey, the Rhesus macaque, were conducted by John C. Beck and colleagues in Montreal, in the late 1950s.^[46] The study published in 1957, which was conducted on “a 13-year-old male with well-documented hypopituitarism secondary to a crainiophyaryngioma,” found that: “Human and monkey growth hormone resulted in a significant enhancement of nitrogen storage…(and) there was a retention of potassium, phosphorus, calcium, and sodium. …There was a gain in body weight during both periods…. There was a significant increase in urinary excretion of aldosterone during both periods of administration of growth hormone. This was most marked with the human growth hormone…. Impairment of the glucose tolerance curve was evident after 10 days of administration of the human growth hormone. No change in glucose tolerance was demonstrable on the fifth day of administration of monkey growth hormone.” The other study, published in 1958, was conducted on six people: the same subject as the Science paper; an 18 year old male with statural and sexual retardation and a skeletal age of between 13 and 14 years; a 15 year old female with well documented hypopituitarism secondary to a craniopharyngioma; a 53 year old female with carcinoma of the breast and widespread skeletal metastases; a 68 year old female with advanced postmenopausal osteoporosis; and a healthy 24 year old medical student without any clinical or laboratory evidence of systemic disease.

In 1985, unusual cases of Creutzfeldt-Jacob disease were found in individuals that had received cadaver-derived HGH ten to fifteen years previously. Based on the assumption that infectious prions causing the disease were transferred along with the cadaver-derived HGH, cadaver-derived HGH was removed from the market.

In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere.

As of 2005, recombinant growth hormones available in the United States (and their manufacturers) included Nutropin (Genentech), Humatrope (Lilly), Genotropin (Pfizer), Norditropin (Novo), and Saizen (Merck Serono). In 2006, the U.S. Food and Drug Administration (FDA) approved a version of rHGH called Omnitrope (Sandoz). A sustained-release form of growth hormone, Nutropin Depot (Genentech and Alkermes) was approved by the FDA in 1999, allowing for fewer injections (every 2 or 4 weeks instead of daily); however, the product was discontinued by Genentech/Alkermes in 2004 for financial reasons (Nutropin Depot required significantly more resources to produce than the rest of the Nutropin line).

Dietary supplements claiming relation to GH

To capitalize on the idea that GH might be useful to combat aging, companies selling dietary supplements have websites selling products linked to GH in the advertising text, with medical-sounding names described as “HGH Releasers”. Typical ingredients include amino acids, minerals, vitamins, and/or herbal extracts, the combination of which are described as causing the body to make more GH with corresponding beneficial effects. In the United States, because these products are marketed as dietary supplements it is illegal for them to contain GH, which is a drug. Also, under United States law, products sold as dietary supplements cannot have claims that the supplement treats or prevents any disease or condition, and the advertising material must contain a statement that the health claims are not approved by the FDA. The FTC and the FDA do enforce the law when they become aware of violations.

[Note: It is critical and very important to read the paragraph above entitled “Dietary Supplements claiming relation to GH”. This shows why so many height increasing supplements or oral intake formulas are scams by definition. The people don’t realize that selling an amino acid combination does not make it a GH release rate increaser since the hypothalamus is what really controls the anterior pituitary in releasing the compounds.]

Me: This post is one of those must-read ones because this will set up the base knowledge for almost all other article we will write about. I do not wish to go over the entire article above but I will bullet the major point one should take away from the post.

• GH, human chorionic somatomammotropin, and prolactin belong to a group of homologous hormones with growth-promoting and lactogenic activity.
• in structure, GH is evolutionarily homologous to prolactin and chorionic somatomammotropin.
• Several molecular isoforms of GH exist in the pituitary gland and are released to blood.
• Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus. These cells release the peptides Growth hormone-releasing hormone (GHRH or somatocrinin) and Growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal venous blood surrounding the pituitary.
• Somatotropic cells in the anterior pituitary gland then synthesize and secrete GH in a pulsatile manner, in response to these stimuli by the hypothalamus. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep with plasma levels of 13 to 72 ng/mL
• Nearly fifty percent of GH secretion occurs during the third and fourth NREM sleep stages. Surges of secretion during the day occur at 3- to 5-hour intervals
• Young adolescents secrete GH at the rate of about 700 μg/day, while healthy adults secrete GH at the rate of about 400 μg/day.
• Stimulators of growth hormone (GH) secretion include GHRH (somatocrinin), ghrelin, clonidine and L-DOPA by stimulating GHRH release, hypoglycemia, arginine and propranolol, niacin as nicotinic acid (Vitamin B3), vigorous exercise
• Like most other protein hormones, GH acts by interacting with a specific receptor on the surface of cells.
• Increased height during childhood is the most widely known effect of GH. Height appears to be stimulated by at least two mechanisms:
• 1. Because polypeptide hormones are not fat-soluble, they cannot penetrate sarcolemma. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway. Through this mechanism GH directly stimulates division and multiplication of chondrocytes ofcartilage.
• 2. GH also stimulates, through the JAK-STAT signaling pathway, the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it what appears to be both an endocrine and anautocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.
• In addition to increasing height in children and adolescents, growth hormone has many other effects on the body:
• 1. Increases calcium retention, and strengthens and increases the mineralization of bone
• 2. Increases muscle mass through sarcomere hyperplasia
• 3. Promotes lipolysis
• 4. Increases protein synthesis
• 5. Stimulates the growth of all internal organs excluding the brain
• 6. Plays a role in homeostasis
• 7. Reduces liver uptake of glucose
• 8. Promotes gluconeogenesis in the liver
• 9. Contributes to the maintenance and function of pancreatic islets
• 10. Stimulates the immune system
• Prolonged GH excess thickens the bones of the jaw, fingers and toes. Resulting heaviness of the jaw and increased size of digits is referred to as acromegaly.
• results are not as dramatic when compared to short stature that is solely attributable to deficiency of GH
• Use of GH as a drug has been approved by the FDA for several indications. This means that the drug has acceptable safety in light of its benefits when used in the approved way.
• As of 2005, recombinant growth hormones available in the United States (and their manufacturers) included Nutropin (Genentech), Humatrope (Lilly), Genotropin (Pfizer), Norditropin (Novo), and Saizen (Merck Serono). In 2006, the U.S. Food and Drug Administration (FDA) approved a version of rHGH called Omnitrope (Sandoz). A sustained-release form of growth hormone, Nutropin Depot (Genentech and Alkermes) was approved by the FDA in 1999, allowing for fewer injections (every 2 or 4 weeks instead of daily)

This is the first in a series of posts where I really go deep in the study and analysis of the main body parts or body chemical signals that occur in the body in the natural height growth process. I know I have already talked about these topic extensively already but I have never focused completely on the topic I will get into. I will focus on the epiphyseal growth plates in this post.

First, a quick intro from Wikipedia (source HERE)

Epiphyseal plate

Me: So the growth plate is not just 1 layer of cartilage. There is actually 5 layers which start from the epiphysis of the long bone and goes in the metaphysis of the long bone. So the layering order is Epiphysis–>Resting zone–>Proliferative zone–> Hypertrophic zone–> Calcified zone–>Ossification Zone–>Metaphysis. 

The growth plates is made of mainly a type of cartilage called hyaline cartilage. The actual cartilage is an actual matrix of three main components, chondocytes, collagen, and proteoglycans. The cartilage’s cells is the chondrocyte. Chondrocytes are the cells that go through the process of mitosis and split into two same cells over and over again. The increased number of cells increases usually at a set rate, which is the real rate of long bone longitudinal growth aka rate of height increase or height growth. As the chondrocytes multiply and increase in number the old cells get pushed in in the metaphysis direction towards the hypertrophic cartilage zone. while the newly formed chondrocyte cells gets pushed to the epiphysis direction, towards the resting zone.

Let’s study further on using the Wikipedia article on Endochondral Ossification (located HERE)

Histology

During endochondral ossification, five distinct zones can be seen at the light-microscope level.

1. Zone of resting cartilage. This zone contains normal, resting hyaline cartilage.
2. Zone of proliferation / cell columns. In this zone, chondrocytes undergo rapid mitosis, forming distinctive looking stacks.
3. Zone of maturation / hypertrophy. It is during this zone that the chondrocytes undergo hypertrophy (become enlarged). Chondrocytes contain large amounts of glycogen and begin to secrete alkaline phosphatase.
4. Zone of calcification. In this zone, chondrocytes are either dying or dead, leaving cavities that will later become invaded by bone-forming cells. Chondrocytes here die when they can no longer receive nutrients or eliminate wastes via diffusion. This is because the calcified matrix is much less hydrated than hyaline cartilage.
5. Zone of ossification. Osteoprogenitor cells invade the area and differentiate into osteoblasts, which elaborate matrix that becomes calcified on the surface of calcified cartilage. This is followed by resorption of the calcified cartilage/calcified bone complex.

Growth of the cartilage model

The cartilage model will grow in length by continuous cell division of chondrocytes, which is accompanied by further secretion of extracellular matrix. This is called interstitial growth. The process of appositional growth occurs when the cartilage model also grows in thickness due to the addition of more extracellular matrix on the peripheral cartilage surface, which is accompanied by new chondroblasts that develop from the perichondrium.

Primary center of ossification

• Formation of periosteum: The perichondrium becomes the periosteum. The periosteum contains a layer of undifferentiated cells (osteoprogenitor cells) which later become osteoblasts.
• Formation of bone collar: The osteoblasts secrete osteoid against the shaft of the cartilage model (Appositional Growth). This serves as support for the new bone.
• Calcification of matrix: Chondrocytes in the primary center of ossification begin to grow (hypertrophy). They stop secreting collagen and other proteoglycans and begin secreting alkaline phosphatase, an enzyme essential for mineral deposition. Then calcification of the matrix occurs and apoptosis of the hypertrophic chondrocytes occurs. This creates cavities within the bone. The exact mechanism of chondrocyte hypertrophy and apoptosis is currently unknown.
• Invasion of periosteal bud: The hypertrophic chondrocytes (before apoptosis) secrete Vascular Endothelial Cell Growth Factor that induces the sprouting of blood vessels from the perichondrium. Blood vessels forming the periosteal bud invade the cavity left by the chondrocytes and branch in opposite directions along the length of the shaft. The blood vessels carry hemopoietic cells, osteoprogenitor cells and other cells inside the cavity. The hemopoietic cells will later form the bone marrow.
• Formation of trabeculae: Osteoblasts, differentiated from the osteoprogenitor cells that entered the cavity via the periosteal bud, use the calcified matrix as a scaffold and begin to secrete osteoid, which forms the bonetrabecula. Osteoclasts, formed from macrophages, break down spongy bone to form the medullary (bone marrow) cavity.

Secondary center of ossification

About the time of birth, a secondary ossification center appears in each end (epiphysis) of long bones. Periosteal buds carry mesenchyme and blood vessels in and the process is similar to that occurring in a primary ossification center. The cartilage between the primary and secondary ossification centers is called the epiphyseal plate, and it continues to form new cartilage, which is replaced by bone, a process that results in an increase in length of the bone. Growth continues until the individual is about 26 years old or until the cartilage in the plate is replaced by bone. The point of union of the primary and secondary ossification centers is called the epiphyseal line.

Appositional bone growth

The growth in diameter of bones around the diaphysis occurs by deposition of bone beneath the periosteum. Osteoclasts in the interior cavity continue to degrade bone until its ultimate thickness is achieved, at which point the rate of formation on the outside and degradation from the inside is constant.

Me: It is important to understand what is hypertrophy (source)

Hypertrophy (from Greek ὑπέρ “excess” + τροφή “nourishment”) is the increase in the volume of an organ or tissue due to the enlargement of its component cells.

Me: I strongly suggest the reader who is not familiar with the physiology of the growth plate to read and understand the information  above. The most interesting thing stated on Wikipedia is that the mechanism for why or how the chondrocytes go through hypertrophy and apoptosis is still not known at this time. 

The life of a chondrocyte starts really from a the progenitor which is the mesenchymal stem cell. From source,…

Undifferentiated mesenchymal stem cell lose their process, proliferate and crowd together in a dense aggregate of chondrogenic cells(cartilage) at the center of chondrification. These condrogenic cells will then differentiate to chondroblasts which will then to synthesize the cartilage ECM(extra cellular matrix). Which consists of ground substance(proteoglycans, glycosaminoglycans for low osmotic potential) and fibers. The chondroblasts then trap themselves in a small space that is no longer in contact with the newly created matrix called lacunae which contain extracellular fluid. The chondroblast is now a chondrocyte, which is usually inactive but can still secrete and degrade matrix depending on the conditions. The majority of the cartilage that has been built has been synthesized from the chondroblast which are much more inactive at a late age (adult hood) compared to earlier years (pre-pubesence)

Me: When the newly formed chondrocyte is from mitosis of existing chondrocytes in the proliferate zone, they first get pushed to the resting zone. They release as waste the collagen and proteoglycan which forms the matrix of the hyaline cartilage. The stacking of the cells from the mitosis process of the proliferative zone seems to cause the original chondrocytes to get pushed away from the proliferative zone. into the hyper trophic zone where the cells stop releasing collagen or proteoglycan. secreting alkaline phosphatase, an enzyme essential for mineral deposition. Then calcification of the matrix occurs and apoptosis of the hypertrophic chondrocytes occurs. The reason for the chondrocytes apoptosis is believed because they have been pushed too far away from the nutrient rich blood vessel areas of the cartilage of the plate.

The cells have now been pushed to the calcification zone and the cells are either already dead or dying. This creates cavities within the bone which eventually gets filled up by the osteoblasts. The osteoblasts use the calcified matrix as a scaffold and begin to secrete osteoid, which forms the bonetrabecula. Osteoclasts, formed from macrophages, break down spongy bone to form the medullary (bone marrow) cavity.

From Duke Health, we learn that

1. On average, females are done growing around age 12 to 14, and boys around age 14 to 16.

2. Most children grow an average of two years after they have completed their pubertal growth spurt.

From a previous article I wrote about the different cartilages and when they close, it turns out the cartilage in our torso of the vertebrate do not completely ossify when the long bone’s growth plates fuse, at least by 2 years. So even if your X-rays from your doctor come back saying your growth plates are fused, they haven’t checked the cartilage in your vertebrate and your torso.

This means that Boys and Girls will actually stop increasing in by +4 years of what was stated above. So males stop increasing in height around the 18-20 year marks, while the Females stop increasing in height around the 16-18 year mark.

From the University of Pennsylvania website HERE….

It likewise grows and expands centrifugally in all directions, although much more slowly than did the primary center. As the distance between the growth plate and the epiphysis gradually decreases, the portion of the epiphysis that faces the growth plate closes and becomes sealed with condensed bone, termed the terminal bone plate or simply the bone plate.(78)Thereafter the epiphysis assumes a somewhat flattened hemispheric appearance and slowly fills out the remaining end of the long bone.

the growth plate may be divided anatomically into three components: a cartilaginous component, itself divided into various histologic zones; a bony component, or metaphysis; and a fibrous component surrounding the periphery of the plate comprising the groove of Ranvier and the perichondrial ring of LaCroix. How the growth plate synchronizes chondrogenesis with osteogenesis or interstitial cartilage growth with appositional bone growth at the same that it is growing in width, bearing load, and responding to local and systemic forces and factors is a fascinating phenomenon the key features of which are only beginning to be understood at the present time.

Me: What seems to be the big problem is that the process of human growth, or longitudinal lengthen increasing is not fully understood, but only at a very basic level. There is still a lot that researchers and scientists don’t understand. They know that the human body is going through two major processes at the same time. One is chondrogenesis or the creation and division of chondrocytes. At the same time, the process of osteogenesis (the creation and growth of bone) is occurring too right next to it making the entire process of going from the initial chondrocytes into the eventual bone component is done smoothly. 

[Note: This article post is turning out to be far longer and more deep in study than I expected so I decided to stop it right here and continue on the study of the growth plate in a later post. ]

I had sent an email to Tyler Of HeightQuest.Com maybe 1 month ago about what types of disorders and pathologies I should study to understand the human growth process better. He has referred me to Enchondrodysplasia nad Ollier’s Disease for study. So today I wanted to look into the condition called Ollier’s disease to see who it affects a person, and what we can take away from it for our height increase endeavors.

From the US National Library of Medicine , National Institutes of Health website located HERE . Again the important parts are highlighted.

Journal List >Orphanet J Rare Dis >v.1; 2006 >PMC1592482

Orphanet J Rare Dis. 2006; 1: 37.

Published online 2006 September 22. doi:  10.1186/1750-1172-1-37

PMCID: PMC1592482

Ollier disease

Caroline Silve¹ and Harald Jüppner²

Author information ► Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

Abstract

Enchondromas are common intraosseous, usually benign cartilaginous tumors, that develop in close proximity to growth plate cartilage. When multiple enchondromas are present, the condition is called enchondromatosis also known as Ollier disease (WHO terminology). The estimated prevalence of Ollier disease is 1/100,000. Clinical manifestations often appear in the first decade of life. Ollier disease is characterized by an asymmetric distribution of cartilage lesions and these can be extremely variable (in terms of size, number, location, evolution of enchondromas, age of onset and of diagnosis, requirement for surgery). Clinical problems caused by enchondromas include skeletal deformities, limb-length discrepancy, and the potential risk for malignant change to chondrosarcoma. The condition in which multiple enchondromatosis is associated with soft tissue hemangiomas is known as Maffucci syndrome. Until now both Ollier disease and Maffucci syndrome have only occurred in isolated patients and not familial. It remains uncertain whether the disorder is caused by a single gene defect or by combinations of (germ-line and/or somatic) mutations. The diagnosis is based on clinical and conventional radiological evaluations. Histological analysis has a limited role and is mainly used if malignancy is suspected. There is no medical treatment for enchondromatosis. Surgery is indicated in case of complications (pathological fractures, growth defect, malignant transformation). The prognosis for Ollier disease is difficult to assess. As is generally the case, forms with an early onset appear more severe. Enchondromas in Ollier disease present a risk of malignant transformation of enchondromas into chondrosarcomas.

Disease name/synonyms

Ollier disease

Enchondromatosis

Multiple enchondromatosis

Dyschondroplasia

Definition

Enchondromas are common benign usually asymptomatic cartilage tumors, which develop in the metaphyses and may become incorporated into the diaphyses of long tubular bones, in close proximity to growth plate cartilage . Enchondromatosis (OMIM 166000) or Ollier disease (World Health Organization terminology) is defined by the presence multiple enchondromas and characterized by an asymmetric distribution of cartilage lesions that can be extremely variable (in terms of size, number, location, evolution of enchondromas, age of onset and of diagnosis, requirement for surgery).

The condition in which multiple enchondromatosis is associated with soft tissue hemangiomas is known as Maffucci syndrome.

Epidemiology

The estimated prevalence of Ollier disease is 1/100,000.

Clinical description

Clinical manifestations in Ollier disease often appear in the first decade of life and usually start with the appearance of palpable bony masses on a finger or a toe, an asymetric shortening of an extremity with limping, osseous deformities associated or not with pathologic fractures. Upon physical examination, enchondromas present on the extremities are usually visible as masses embedded within phalanges, metacarpal and metatarsal bones. Enchondromas frequently affect the long tubular bones, particularly the tibia, the femur, and/or the fibula; flat bones, especially the pelvis, can also be affected. The lesions may affect multiple bones and are usually asymetrically distributed, exclusively or predominantly affecting one side of the body. Affected bones are often shortened and deformed. Indeed, bone shortening may be the only clinical sign of the disease. These bone shortenings are often associated with bone bending and curving, and may lead to limitations in articular movement. Forearm deformities are frequently encountered and these are similar to those observed in hereditary multiple exostosis (HME). The trunc is usually not affected, except for rib enchondromas and scoliosis resulting from pelvis imbalance. In childhood, the lesions are subjected to pathologic fractures.

Clinical forms

While enchondromatosis had been recognized for a long time, Ollier at the end of the 19th century (thus the name of Ollier’s or Ollier disease to designate the condition) emphasized the asymetrical and random distribution of enchondromas. Some authors distinguish two subtypes of enchondromatosis, enchondromatosis and Ollier disease. The first form affects mostly men. It is characterized by enchondromas located mainly at the extremities and appears to be transmitted in an autosomal dominant fashion. The second form affects mostly women. It is characterized by an unilateral distribution of enchondromas and appears sporadic. However, the basis for this classification into two forms is not supported by a thorough analysis of available clinical reports. In all instances, the association of multiple enchondromas with hemangiomas is referred to as Maffucci syndrome. Recently, a previously unreported form in which there is extensive involvement of the epiphyseal and metaphyseal regions of long bones of the lower extremity has been described .

Radiography

Enchondromas are rarely observed at birth, although the lesions are most likely already present. Roentgenograms typically show multiple, radiolucent, homogenous lesions with an oval or elongated shape and well defined slightly thickened bony margin. The lesions and long bone axis run parallel (Figure (Figure1).1). The lesions usually calcify with time and become diffusely punctated or stippled, a light trabeculation may be visible. Enchondromas are frequently assembled as clusters, thus resulting in the metaphyseal widening. When localized at the bone border, the enchondromas produce a typical notch-like image. A minor delay in bone age, on average 0.6 +/- 1.3 years, has been reported in children affected by Ollier disease.

Roentgenographs showing enchondromas localized in the upper part of the humerus (fig 1a and lower part of the radius (fig 1b) of a girl 7 years of age affected with Ollier disease. Courtesy of Dr Fitoussi, Hôpital Robert Debré, Paris,

Enchondromas are almost exclusively localized in the metaphysis of long bones and in the small bones of the hands and feet. They are initially localized close to the growth plate cartilage and then migrate progressively towards the diaphysis. The epiphyseal region next to an affected metaphysis may show irregularities.

Again, it is important to emphasize the irregular distribution of the lesions, which can be localized to one limb, or limited to one half of the body; however, even limited largely to one side of the body, one or two enchondromas are frequently present on the other side, in particular in the hand bones. If lesions are distributed over the entire body, one side is typically more affected. In the hands, the lesions almost never affect all metacarpal bones and phalanges.

Enchondromas result in severe growth abnormalities (more severe than those observed in multiple exostosis). Affected diaphysis are short and massively enlarged, and these may show bending close to the metaphysis. Ulnar shortening is usually more relevant than shortening of the radius; fingers often show irregular sizes. Signs of pathological fractures may be present.

Signs of malignant transformation should be looked for, as it is a major complication of enchondromatosis. These signs include cortical erosion, extension of the tumor into soft tissues, and irregularity or indistinctness of the surface of the tumor. Indeed, enchondromas tend to be well circumscribed, whereas chondrosarcomas show poor demarcation. The pattern of mineralization is also important in differentiating enchondromas from chondrosarcomas. As mentioned above, enchondromas tend to show a uniform pattern of mineralization, and the presence of unmineralized parts in the lesion is suspicious.

Histopathology

Macroscopic examination of enchondromas usually shows multiple oval-shaped or round cartilaginous nodules in osseous portions of bone. The individual nodules are limited at their periphery by woven or lamellar bone, and are separated from each other by intertrabecular marrow spaces. The cartilaginous tumor matrix is usually solid, with myxoid changes, which manifest as frayings of the matrix. Enchondromas are characterized by the presence of a striking heterogeneity and diversity in the degree of cellularity and chondrocyte phenotype. This heterogeneity depends to some extent on factors such as localization and the patient’s age. In part due to this important cellular heterogeneity, the distinction between benign enchondromas and malignant chondrosarcomas by histochemical criteria is difficult. The histological criteria for malignancy that are used for conventional chondrosarcoma can not be used in Ollier disease because of the increased cellularity, and therefore the distinction between enchondroma and grade I chondrosarcoma in the context of enchondromatosis is extremely difficult or even impossible. The diagnosis therefore relies on the combination of radiographical (cortical destruction, soft tissue extension), clinical and histological criteria.

Etiology and pathogenesis

Endochondral bone ossification is a highly regulated process, which requires the progression of undifferentiated mesenchymal cells into hypertrophic chondrocytes and the subsequent replacement of a cartilaginous matrix by mineralized bone . Enchondromas develop in the metaphysis of long tubular bones in close proximity to the growth plate. Consequently, it was proposed that they result from abnormalities in signaling pathways controlling the proliferation and differentiation of chondrocytes, leading to the development of intraosseous cartilaginous foci.

Genetics

Ollier disease – and Maffucci syndrome – are usually non-familial disorders, and both disorders thus appear to occur spontaneously and are not inherited. The irregular distribution of the lesions in Ollier disease strongly suggests that it is a disorder of endochondral bone formation that occurs due to a post-zygotic somatic mutation that results in mosaism. In two instances, enchondromatosis has been observed in the sons of fathers who presented with mild skeletal dysplasia but without evidence of enchondromas. In one of these cases, a heterozygous mutation (R150C) in the PTH/PTHrP receptor (PTHR1 gene) was inherited from the father.

Parathyroid hormone-related protein (PTHrP) and Indian Hedgehog (IHH) acting on their respective receptors PTHR1 and PTCH1 exert a tightly coupled signaling relay, which is critical for the regulation of endochondral ossification (Figure (Figure2).2). A mutant PTHR1 (R150C) was found to be expressed in the enchondromas from two of six unrelated patients with enchondromatosis. The mutation was found on one parental allele in one patient and his father, who presented with atypical mild skeletal dysplasia, but not with enchondromatosis. However, neither the R150C mutation (26 tumors) nor any other mutation in the PTHR1 gene (11 patients) could be identified in another study, suggesting heterogeneity of the molecular defect(s) leading to enchondromatosis.

Importance of IHH and PTHrP signaling in the modulation of chondrocyte proliferation and differentiation during endochondral bone formation. PTHrP is synthesized by chondrocytes and perichondrial cells in the periarticular growth plate. PTHrP diffuses

The mutant PTHR1 (R150C) seems to constitutively activate the PTHrP-dependent pathway, thus decreasing chondrocyte differentiation, thereby leading to the formation of enchondromas . Consistent with this conclusion, transgenic mice expressing the mutant PTHR1 under the control of the collagen type II promoter develop tumors that are similar to those observed in human enchondromatosis. Because regulation of Ihh by PTHrP was found to be lost in these enchondromas, additional transgenic mice were generated that overexpress the Hedgehog (Hh) transcriptional regulator, Gli2. These mice develop ectopic cartilaginous islands similar to those observed in the mice expressing the mutant PTHR1. Thus, the Ihh signaling pathway as a whole seems to play a crucial role in the formation of enchondromatosis.

Cytogenetics and molecular genetics

There are few cytogenetic reports of benign enchondromas, but there are no tumor-specific chromosomes or chromosomal regions associated with enchondromas, or chondrosarcomas.

Little is known about the molecular mechanisms involved in the malignant transformation from enchondromas to chondrosarcomas. Expression of PTHrP, the PTHR1, and their downstream partner Bcl2 may be correlated with the grade of malignancy in chondrosarcoma.

Diagnostic methods

The diagnosis of Ollier disease is based on clinical and conventional radiological evaluations. Histological analysis has a limited role and is mainly used if malignancy is suspected. Additional investigations, such as scintigraphy, ultrasound, magnetic resonance imaging (MRI) are not useful for establishing the diagnosis. They are indicated for the evaluation and surveillance of lesions that become symptomatic (pain, increase in size).

Differential diagnosis

Ollier disease must be differentiated from HME. HME is an autosomal dominant disorder characterized by multiple bone tumors capped by cartilage, that occur mostly in the metaphyses of long bones. To establish the diagnosis of either disease, clinical and radiological criteria are used. The most important criterium to distinguish enchondromas from osteochondromas as seen in HME is the localization of bone lesions: osteochondromas are located at the bone surface and enchondromas are located in the center of bones, thus allowing radiographic distinction.

Other rare forms of chondromatosis, which include metachondromatosis, spondyloenchondroplasia and genochondromatosis type I and II, are described and have been well defined.

Genetic counseling

Ollier disease – and Maffucci syndrome – are usually sporadic, non-familial disorders.

Treatment

There is no medical treatment for Ollier disease. Surgery is indicated in case of complications (pathological fractures, growth defect, malignant transformation).

Prognosis

The prognosis of Ollier disease is difficult to assess. Patient with numerous lesions may have a better prognosis than patients with localized cartilaginous changes, which may induce major shortening of a lower extremity and thus limb asymmetry, especially if already present in a very young child. Similarly, early development of enchondromas in phalanges may lead to major finger deformities. As is generally the case, forms with an early onset appear more severe. Neural compressions are less frequently observed than in HME. Enchondromas in Ollier disease present a risk of malignant transformation of enchondromas into chondrosarcomas, which usually occurs in young adults, and thus at an earlier age than observed in patients with chondrosarcoma alone. The reported incidence of malignant transformation is variable and estimated to occur in 5–50% of the cases . It is higher in Maffucci’s syndrome, the prognosis of which is more severe than that of Ollier disease. Association of Ollier disease with other tumors has been reported.

Unresolved questions

• Although an identical heterozygous mutation in the PTHR1 gene has been identified in two unrelated patients with Ollier disease, this or other mutations in this gene were not identified in additional patients with this disorder. Although these studies need to be extended, they suggest that the cause of Ollier disease is heterogenous and raise the possibility that two (or more) genetic mutations are required to develop the disease. The development of enchondromas could thus be caused by a germline mutation associated with a somatic mosaic mutation. Furthermore, additional mutational events may underly progression from enchondromas to tumors.

• The molecular mechanisms involved in malignant transformation are unknown.

• The link, if any, between Ollier disease and Maffucci syndrome is unknown

Me: Here is the main take aways from the study of Ollier’s Disease. Enchondromas are common intraosseous, usually benign cartilaginous tumors, that develop in close proximity to growth plate cartilage. When multiple enchondromas are present, the condition is called enchondromatosis or Ollier’s Disease. It was proposed that they result from abnormalities in signaling pathways controlling the proliferation and differentiation of chondrocytes, leading to the development of intraosseous cartilaginous foci. Affected bones are often shortened and deformed. Indeed, bone shortening may be the only clinical sign of the disease. These bone shortenings are often associated with bone bending and curving, and may lead to limitations in articular movement. Forearm deformities are frequently encountered. A mutant PTHR1 (R150C) was found to be expressed in the enchondromas from two of six unrelated patients with enchondromatosis. The mutant PTHR1 (R150C) seems to constitutively activate the PTHrP-dependent pathway, thus decreasing chondrocyte differentiation, thereby leading to the formation of enchondromas.

Theoretically the study of why and how the enchondromas develop can help possibly prevent the activation of of them causing limb deformities and limb stunting. On the flip side, an understanding of how these usually benine tumors develop around the growth plate area may give us a clue on the signal pathway of them which might give us a clue on how to recreate and regrow another layer of growth plates in our original growth plate area using the very enchondromas which would allow for continued growth if we can control the enchondromas and prevent the tumor from becoming malignant.