HGH is a hormone produced by the pituitary gland

HGH and HGH Fragment: What Are They and How Do They Differ?

Understanding how human growth hormone (HGH) fragments relate to HGH can be a confusing topic for some, especially in cases where very similar molecules are referred to by different names. At first, it may seem counterintuitive that a compound called โ€œHGH fragmentโ€ does not promote growth and that its biological activity should differ substantially from that of HGH. This article attempts to clarify the topic of HGH and its related fragments by covering how this hormone was first discovered, the importance of studying fragments, what the full-length hormone and fragments do, and how they are used therapeutically.

The History of HGH

Discovery

The pituitary gland was first linked to growth in 1887, when Minkowski found that it was associated with growth disorders. Research continued, with researchers discovering that extracts from bovine pituitary glands, when injected into rats, could cause excess growth. Separate experiments strengthened the link by demonstrating that removing the pituitary could halt growth. Between the 1940s and 1950s, researchers successfully isolated the hormone responsible from bovine and porcine pituitary glands, and it was referred to as growth hormone or somatotropin.

The Need for Human-Derived Growth Hormone

Although this hormone demonstrated effects on growth in some animals, they were ineffective in humans. Researchers then isolated human growth hormone from the pituitary glands of cadavers and, in 1958, used HGH in the first successful treatment of pituitary dwarfism in a 17-year-old boy. This was later deemed an unsafe source of HGH after some patients who received growth hormone treatment developed Creutzfeldt-Jakob disease from contaminated preparations.

Instead, HGH is now produced using recombinant DNA technology. Essentially, the human gene is cloned and inserted into bacteria, which produce the hormone in mass quantities. This is then purified before use.

The Significance of Structure and Sequences

The Full-Length Hormone

HGH is a 191-amino acid-long hormone produced by the pituitary gland. When we look at the three-dimensional structure of this hormone, we can see that its core is made up of four alpha helices that allow it to bind to receptors. Its target receptors are found on the surface of cells such as muscle, bone, and cartilage cells. Once bound to its receptor, it activates signalling pathways that alter gene transcription, protein synthesis, and cellular growth.

HGH Fragments

Researchers have found that specific portions, or fragments, of a hormoneโ€™s sequence correspond to different biological effects. In the case of HGH, some fragments occur naturally, such as HGH 1-43 and HGH 44-191. These are thought to be created through a natural process of proteolysis. There are also artificially synthesised fragments. These fragments were synthesised by researchers in order to better understand how HGH functions as a whole and explore the potential therapeutic applications of the different domains. The most notable fragment is HGH 176-191. A modified version of this fragment, AOD 9604, is used for research purposes due to its improved stability and activity.

We will begin by taking a look at the activity of the full-length hormone before moving on to the fragments.

Biological Effects of HGH

Growth and Development

As the name would suggest, HGH significantly influences growth and development. During childhood and puberty, it stimulates longitudinal bone growth through the GH-insulin-like growth factor 1 (IGF-1) axis. It is known to produce an increase in muscle mass and to help maintain bone mass1,2.

Its activity is not solely dependent on IGF-1, as it also acts directly on bone tissue to increase bone mass and quality3.

Metabolism

Its role in metabolism is not straightforward, as the effects it exerts depend on metabolic state. For example, if fed and well nourished, HGH promotes anabolic processes that support lean body mass and glycogen storage via IGF-1 and insulin stimulation.

In a fasted state or during metabolic stress, it promotes lipolysis and preserves protein4. Although lipolysis can be seen as beneficial to those with the goal of weight loss, the excess of FFAs in non-fat tissues, such as the liver, muscles, and pancreas, can lead to the production of toxic lipid byproducts, triggering oxidative stress and inflammation. This lipotoxicity can disrupt insulin signalling pathways, impair mitochondrial function, and block glucose entry. Put more simply, it induces insulin resistance. This effect on metabolism is also seen in those with chronically high GH5.

It also acts on the brain to regulate food intake, energy expenditure, and glucose homeostasis, especially under conditions of metabolic stress, such as fasting or exercise6,7.

Tissue Repair and Maintenance

HGH promotes tissue repair and maintenance by enhancing cell proliferation, angiogenesis, and collagen synthesis, all of which are important in wound healing and tissue regeneration8. In skeletal muscle and tendon, HGH stimulates matrix collagen synthesis, strengthening the extracellular matrix, which is important for tissue regeneration. HGH is linked to an increase in muscle mass but does not directly affect myofibrillar protein synthesis9. Instead, HGHโ€™s stimulation of IGF-1 production by the liver is what promotes the growth of this type of cell2.

Consequences of Deficiency and Excess

The overexpression of HGH can result in several systemic effects, such as:

  • Enhanced growth and increased body size (acromegaly)10
  • Metabolic disturbances, including hyperphagia, hyperinsulinemia, and insulin resistance11,12
  • Joint degeneration13
  • Enhancement of fibroblast proliferation, migration, and collagen formation8
  • Disruption of endocrine and reproductive functions10
  • Increased bone resorption and decreased cortical thickness leading to problems with bone architecture and mechanical strength14
  • Tumour progression and immune-desert tumour microenvironment15,16

In cases of growth hormone deficiency (GHD), gene expression is disrupted in multiple tissues, contributing to effects such as:

  • Growth failure in children, leading to short stature17
  • Decreased muscle mass and reduced exercise capacity18
  • Increased visceral fat and unfavourable lipid profiles18
  • Osteoporosis18
  • Neurocognitive impairments19
  • Abnormal glucose metabolism20
  • Poor quality of life and increased mortality risk18,20

Therapeutic Use

Clearly, an excess or deficiency in growth hormone is best avoided. In cases of deficiency, carefully controlled doses of growth hormone can help to normalise growth. As such, HGH is used in the treatment of:

  • GH Deficiency: In children with GHD, HGH corrects growth and enables them to reach normal adult height21. In adults with GHD, including those who have had pituitary tumour surgery, HGH replacement helps to improve body composition by decreasing body fat and increasing lean mass. It also improves lipid profiles, bone metabolism, exercise capacity, and quality of life22.
  • Non-GH-Deficient Short Stature: In many countries, HGH is licensed to improve adult height in children who are short for reasons other than GH deficiency, such as Turner syndrome, SHOX deficiency, Noonan syndrome, and Prader-Willi syndrome. It is also used on children who are small for their gestational age, have idiopathic short stature, or have chronic kidney disease related to their short stature23.

Because of its regenerative properties and ability to influence metabolism, researchers have investigated its potential to:

  • Support muscle repair by increasing neovascularisation and satellite cell activation: There is hope that this could help to accelerate recovery after injury24. It is important to note that despite its ability to support muscle repair, HGH does not consistently enhance the proliferation of human tendon and ligament fibroblasts, suggesting that it may have variable effects depending on tissue type25.
  • Improve body composition in obese individuals: A decrease in visceral fat, an increase in lean body mass, and improved lipid profiles have been observed in human studies26.

Risks

When used as part of a medically supervised therapy, HGH use can involve certain risks27,28. Common risks associated with short-term use include:

  • Injection site pain/haematoma
  • Rash
  • Oedema
  • Arthralgia
  • Transient fever
  • Prepubertal gynecomastia

Less common risks include:

  • Intracranial hypertension (benign)
  • Slipped capital femoral epiphysis
  • Progression of scoliosis
  • Fluid retention
  • Headache

Short-term HGH treatment tends to increase insulin sensitivity, but this is not always the case and appears to happen only in certain populations and depends on the dose given and the age of the person taking it.

Long-term use of HGH involves additional risks, including:

  • Cancer/second neoplasms: The risk of second tumours is higher in those who have previously been irradiated or who have a genetic predisposition to developing cancer29. GH is not advised for those who have active cancers and should be used with caution after remission. One study showed that when applied to ageing tissues, it suppressed DNA repair and promoted chromosomal instability. This could impair tissue maintenance and promote pathological changes30, yet there is no clear increase in the incidence of cancer in those who have had no prior malignancy31.
  • Cardio-/cerebrovascular disease: Although overall mortality has not been shown to increase, some studies suggest an increased cardiovascular/cerebrovascular risk32. It is important to note that it is difficult to determine whether these links are relevant for all populations since many of the studies reporting these findings report the results of HGH treatment on people who have underlying conditions that cause short stature and who may have had prior treatments, which can increase their risk of health problems.
  • Glucose metabolism/diabetes: GH increases insulin resistance and modestly increases type 2 diabetes risk, particularly in children with obesity or other risk factors33. In adults with GHD and no major comorbidities, long-term GH replacement therapy does not seem to increase the risk of diabetes, CVD, or tumour incidence34.
  • Endocrine disorders: It can sometimes worsen latent adrenal and thyroid insufficiency, so reassessment is important after starting HGH therapy31.

Overall, HGH is considered safe when used at recommended doses for the treatment of approved indications. Given the fact that the body may respond adversely to HGH, careful monitoring is advisable.

HGH Fragment

The Importance of Studying Fragments

Earlier in this article, we looked briefly at hormone fragments, how some are natural while others are synthesised. Studying the fragments that make up a hormone helps researchers to:

  • Identify new biological roles: Some fragments of hormones that were originally dismissed as โ€œjunkโ€ have later been found to exert significant biological activity. Instead of simply dismissing a fragment as a product of proteolysis, by studying them, we may find that they serve some useful function.
  • Understand structure-function relationships: We know that certain portions of amino acid sequences correspond to different 3D structures that are created when a protein folds into its functional shape. By studying each fragment, researchers can better understand the activity of each of these domains, as they may have distinct or opposing biological activities.
  • Improving diagnosis and treatments: Some hormone fragments are associated with pathologies, the detection of which can help in discovering the disease and monitoring its progression. Some fragments may have activities that researchers hope can be used for the treatment of diseases due to their specific actions and potentially reduced side effects.
  • Elucidating physiological processes: The presence of fragments suggests that protein hormones might have far more complex modes of action than we previously thought. By studying them, we can understand the additional roles that a hormone may play in signalling.

HGH Fragments

Now that we can appreciate the potential value of fragments, we will take a closer look at fragments derived from HGH:

  • HGH 176-191: A naturally occurring fragment, originally recreated synthetically and named AOD 9401. This fragment was then modified to include a tyrosine residue at the N-terminal, which conferred extra stability and better activity. This was named AOD 9604. It is the most well-studied fragment and represents the lipid-mobilising domain of HGH. Studies show that it enhances the breakdown and utilisation of fat35, but because it does not stimulate IGF-1, it does not promote growth or the diabetogenic effects associated with full-length HGH.
  • HGH 1-43: This is a naturally occurring fragment that exhibits potent insulin-potentiating or insulin-like activity36.
  • HGH 44-191: This fragment has a higher diabetogenic activity than HGH but does not stimulate growth37.
  • HGH 6-13: This fragment has insulin-like activity38.
  • HGH 177-191, 178-191, and 179-191: Each of these fragments has varying degrees of influence over blood glucose and insulin levels39.

An isoform of HGH exists that omits amino acids 32-46. This is known as the 20 kDa variant of HGH and has different receptor binding and biological activity. It does not stimulate the release of insulin as much as HGH and has a smaller diabetogenic effect40.

How Fragment 176-191 and Closely Related Fragments Work

Most research on HGH fragments focuses on fragment 176-191 and AOD 9604, the modified synthetic version of fragment 176-191. In this article, they will be referred to as fragment 176-191 from this point, for the sake of simplicity. The effects of this fragment are distinct from HGH, as it does not activate the classic growth hormone receptor pathway or stimulate IGF-1 production. Instead, it:

  • Modulates lipid metabolism by increasing lipolysis and decreasing lipogenesis in adipose tissue41.
  • Older studies found that it could transiently raise blood glucose and sustain elevated insulin levels, reducing insulin sensitivity, although this effect was not lasting42. More recent studies have found that it does not induce insulin resistance or glucose intolerance, even after chronic treatment43.

Therapeutic Applications of Fragments

AOD 9604 has been evaluated for its potential in the following therapeutic areas:

  • Anti-obesity/metabolic therapy: It reduces weight gain and adipose tissue mass in obese mice35. It has been tested in humans for its ability to promote weight loss, with mixed results44.
  • Joint and bone health: Although it does not promote growth, studies have found that it can promote the healing of joints and prevent hormone-driven bone loss45,46.
  • Cancer drug delivery adjunct: This fragment can bind to tumour-related proteins, enhancing and targeting the activity of chemotherapeutic agents, giving it a potential role in drug delivery and tumour targeting47.

Risks

It is difficult to determine the risks involved with the use of this fragment, since no studies detail any adverse effects. This is due to factors such as a lack of research, most data being from preclinical studies, and the absence of long-term data.

Main Differences Between HGH and HGH Fragment

The main differences between full-length HGH and fragment 176-191 are summarised in the table below:

 

HGH Fragment 176-191
Molecular size and structure 191 amino acids long, 4 alpha helices. Core 16 amino acid fragment with added tyrosine, linear structure.
Receptor activity Binds to growth hormone receptors with high affinity, stimulating IGF-1. No growth hormone receptor signalling. Stimulates lipolysis.
IGF-1 stimulation Strong. Minimal/none.
Metabolic effects Complex effects on glucose and lipid metabolism and context-dependent effects on body composition. Increases lipolysis, decreases lipogenesis.
Therapeutic status Approved for the treatment of growth hormone deficiency and syndromes that cause short stature. Currently experimental and not approved for any treatment.
Known risks Tumorigenic activity in cases of active or previous cancer, possible cardio/cerebrovascular risk, and dysregulated glucose metabolism. Insufficient research to identify risks.

HGH has broad, systemic effects, while fragment 176-191 has more specific activity. The fragment does not promote growth to any significant degree and is not associated with the same metabolic problems that full-length HGH is.

Current Limitations and Future Directions

HGH has a well-established role in the treatment of growth hormone deficiency, where treatment regimens with appropriate dosing have been optimised, and adverse effects are understood. HGH fragments are not as well studied, and appropriate dosing and adverse effects are still uncertain.

Although they stimulate natural signalling, this does not mean that administering them comes without risk. Whenever exogenous hormones are administered, they are essentially boosting natural signalling pathways. This can lead to corrections in signalling and subsequent improvements in health, but could also lead to dysregulation of homeostasis, leading to poor health outcomes. Ultimately, the outcome is dependent on individual circumstances, which is why monitoring during treatment is essential.

Based on preliminary results from studies, we have good reason to look forward to the results of further research on fragments, as their distinct signalling could have useful metabolic and healing benefits.

Currently, HGH, fragment 176-191, and similar fragments are banned by the WADA, as they may have the potential to boost athletic performance and pose a risk to the health of athletes.

Conclusion

HGH is a full-length hormone with systemic, growth-promoting, and metabolic effects, while studies on fragment 176-191 and its related C-terminal peptides have demonstrated a far more specific mode of action, independent of the classic growth hormone signalling pathway.

HGHโ€™s use as a treatment for growth disorders is well established, while fragment 176-191 remains experimental, with early tests indicating its potential use for weight loss. Research on fragments consists mainly of preclinical tests, with a very limited number of human studies. The results of these tests point towards exciting theoretical possibilities for their medical application, but the lack of consistent results in clinical tests emphasises the need for more research.

You can buy HGH and AOD 9604 for your research from us.

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