840.119:Human Growth Hormones

Abstract

Human growth hormone is a small protein molecule consisting of 191 amino acids in a single polypeptide chain. Human growth hormone, also known as Somatropin, is the most common hormone secreted by the anterior pituitary gland. The pituitary gland secretes the hormone throughout ones entire life, but at different rates. Rate of production peaks during adolescence when accelerated growth occurs. The level of the hormone in our body decreases by 14% every ten years into old age. Human growth hormone plays a major role in both growth and metabolism. It has both direct and indirect effects on the body. Indirectly, it is mediated by insulin-like growth factor secreted by the liver and promotes growth. Directly, it results of growth hormone binding to its receptor on target cells. For example, when growth hormone stimulates fat cells, they break down triglycerides and suppress their ability to accumulate circulating lipids causing a person not to build up the fat cells. The hormone also has important effects on protein, lipid, and carbohydrate metabolism.

When a person has a pituitary gland that produces little or no growth hormone, the disease is called Hypopituitarism. Originally, human cadavers were used to produce the hormone to treat patients with Hypopituitarism. There were many disadvantages to using this method of biotechnology. First, a large quantity of pituitary glands was needed to supply the hormone and supply did not meet demand. Second, using human cadavers was very costly. Taking these disadvantages into consideration, a new method for producing the hormone was needed.

Later in the site, we will discuss using microbial biotechnology to produce the hormone. We will also be discussing what is new in this specific biotechnology and the scientific approach including the development, products and services, and new improvements in the science. Next, we will discuss all potential impacts of producing the hormone using microbial biotechnology including both positive and negative. Also, any side effects and long term risks will be covered along with ways to decrease or avoid these risks. Lastly, controversial topics will be discussed and will include medical challenges, ethical and societal concerns, and any economical matters that have come up.

Objectives

We are interested in the study and research of the technology involved in the human Growth Hormone development using microbial technology. Specifically, we will be studying the production of the human Growth Hormone through E. Coli bacteria.

State of the Art

As we mentioned before, the need for a new, more effective way to produce the human growth hormone was great due to the many disadvantages of using the human cadavers. Opting to use E. Coli in the production of the hormone had several advantages like lowering the cost of production and higher output. The first commercially available human growth hormone made by using microbial biotechnology was produced in 1985 by scientists at Genetech. This led to possible production of an almost endless supply of this very vital pharmaceutical. The newest goal in the development of the hormone is the administration of the drug. Currently, the drug is only available in the injectable form but they are working on finding an orally ingestible (pill or liquid) form which would make administering the drug easier.

The human growth hormone used to be only given to children with hypopituitarism and other certain types of dwarfism, but we are now finding that there may be a related disease affecting adults that they have termed Adult Growth Hormone Deficiency (AGHD). AGHD has several physical and psychological symptoms including weight gain, muscle weakness, fatigue, withdraw from others, anxiety, and depression. Administering the hormone to these affected adults is helping these symptoms, but also has some potential side effects (also discussed later) like nausea, joint pain, and headache.

Doctors can perform a number of tests to diagnose a HGH deficiency. A provided blood sample allows them to measure the levels of hormones produced by the pituitary gland and also levels of hormones produced by target endocrine glands, which are influenced by the pituitary gland. By utilizing theses tests, doctors can be cretin the proper treatments are provided. Because long term effects of HGH are still unknown, it is important that this product does not arrive in the hands of those who would misuse the hormone.

An HGH deficiency can affect the at any age, So it is necessary to keep up with the demand for healthy Treatment methods. Since cadavers, other hosts, such as plants, have been examined for protein production. Significant material of the correct structure tobacco cell culture, soy seed, and maize seed are showing correct activity relative to that produced by e- coli. However, there are still more test to follow to meet the production potential of the e-coli. An HGH Another new application for the human growth hormone is enhancing milk production in dairy cattle to produce milk yield. The enhanced milk is currently approved on the market and proven that the milk treated with bovine growth hormone does not pose a risk to human health.

Scientific Approach

Microbial Biotechnology Without the ability to recombine and produce HGH in the lab, there would be no way the demands would be met to provide effective treatments for Hypopituitarism. By Creating it in a laboratory setting it can be controlled and produced pure. This should ensure a product with less risk of side effects.

Development Isolating the gene is always the first step. Scientists isolate the hGH-N gene, which is the HGH expressed by the pituitary gland. The host chosen here is E-coli and the vector placed inside. After put into the proper setting, the e-coli is allowed multiply in mass amounts. Because not every cell produced will have the gene, Bacteria displaying the hGH-N gene are isolated for the rest. After going through the purification process, it can then be dehydrated for packing and shipping purposes. At this point dosage can be adjusted for individual patient’s needs.

Products and Services HGH can be and is produced in liquid and powder form, both used for injection. However Oral supplements are also produced, but not as effective. There is a demand for HGH in the body even after the body stops growing and in some cases patients do not acquire Hypopituitarism until mid-adulthood. If further testing proves to provide the assumed efficiency, this could be a marketed service for all ages who suffer from a HGH deficiency.

Improvement An advantage to producing HGH in e-coli as opposed extracting it from cadavers is that it can be mass produced at purer levels and can be controlled in the lab. Production in e-coli will avoid the past complications observed in other hosts, such as animals.

The form in which it is produced can also be improved. Currently both liquid and powder forms seem to be equally effective, however the problem with oral HGH is that most people will not be able to produce the target amount of HGH needed in treatment; therefore it seems that furthering production down that path will not be an improvement.

AT THE PRESENT TIME, THERE IS NO PROVEN REPLACEMENT REGIMEN FOR HUMAN GROWTH HORMONE EXCEPT INJECTABLE HGH

One journal article showed an experiment that was trying to find another way to obtain HGH by extracting the hGH-V gene from placenta. Full term placenta was discovered to contain identical in HGH, However purification to avoid contamination from other placental tissue would have to undergo reproduction methods such as e-coli as well.

(Potential) Impact

By using e-coli, the production can be done in greater quantities with fewer health effects. Improvements in this method of production will provide enough HGH for treatment to a larger mass of people then could be done in the past. There are still high investment costs to produce recombinant HGH and also costs patients a great deal money. With better production methods, there is hope to decrease these costs.

Hypopituitarism is when pituitary (master gland) fails to release its hormones. The severity of a patients condition can range from “not producing enough” (causing minor problems), to “little to no production” at all. It can come with birth, or can be acquired because of a trauma or a tumor. Treatments can also last from several years to permanent dependency on HGH. Because of this it is important to find a safe way to provide enough HGH at the correct dosage (which can adjust over time).

Health conditions also effect dosage a healthy person would use less for treatment, but it can always change. It is important for the product to be pure so it to will not be the cause of other ailments. A potential impact here is that it will be safe enough to administer to all patients, regardless of health conditions.

Because these hormones are created in a lab in bacteria, approval for this process from production to the open market takes years. Though the potential is high, this product will need to undergo complete testing and improvements in production over the years will make the approval process even longer. 1996, FDA regulated this to be marketed to adult patients. Currently, more testing needs to be done on children and adults over 50. A potential impact in this could be that all patients with hypopituitarism could be treated with HGH. However, long term effects are still unknown, even though it seems a safe bet, it is truly unknown.

Associated Risks

Microbial Biotechnology’s Impact on Risk

Positive Impacts

Due to the use of microbial biotechnology in the production of human growth hormones, the risks involved in this type of therapy have been decreased significantly. Prior to recombinant human growth hormone availability, when cadavers were the source of this protein, human growth hormone therapy was associated with Creutzfeldt - Jakob disease, a fatal neurological infection. At this time, approximately 26 of 7,700 recipients of human growth hormones contracted. Many of the cadavers contained prions that caused Creutzfeldt - Jakob disease in the patients. Introduction of microbial biotechnology is credited for this risk elimination.

Negative Impacts

Increased Availability

Interestingly enough, using microbial biotechnology poses a risk in that it makes this product almost limitless. Of course, it would seem that this would not be considered a “problem” or a “risk.” However, a nearly limitless supply has resulted in several legal and medical risks. Prior to the use of microbial biotechnology, there was much less somatropin available. This meant that only children and adults who were seen as severely growth retardant, those who actually had a deficiency in the amount of growth hormone produced by their pituitary gland, were administered the drug. Escherichia coli has made the drug very available, which means that more patients are taking it. Individuals who do not really need the drug are at risk when using it. In many patients, the drug has not been proven to produce desired results. The use of human growth hormone for indications that are not established is a waste of health funds and amounts to exploiting people and exposing them to unnecessary risk. For many patients, there, in fact, appear to be many negative side effects associated with the misuse of the drug.

Though one would assume the use of microbial biotechnology in human growth hormone production would do nothing but benefit the consumers, on further examination, it begins to become apparent that the use of microbial biotechnology, though seemingly beneficial has resulted in economic risks for consumers, health risks for consumers, and legal risks for physicians and pharmaceutical distributors.

Misuse

The most common misuse of this drug is for anti-aging purposes. As we grow older, growth hormone levels in our body decrease. Someone older than sixty has growth hormone levels half that of young adults. Because of this, human growth hormones appeal greatly to older individuals. However, where there is no deficiency, human growth hormone therapy will artificially raise blood levels of the hormone above normal levels, something not recommended.

Potentially serious medical side effects of GH therapy in adults have been clinically tested. Adults and particularly elderly patients receiving growth hormone treatment were found to have a higher mortality rate than similar patients not being treated. It was also concluded that their hospital stays were longer and more intense. Though adults and elderly patients receive this therapy in order to improve their physiques, elderly men, when receiving human growth hormone therapy, are at risk for developing gynecomastia. Gynecomastia, ironically, is associated with obesity. This is a simple demonstration of this drug being misused.

Risks and Legal Issues

Though many physicians seem unaware or unconcerned, the United States Code Title 21 Section 333 prohibits the distribution of human growth hormones to humans for any use other than recognized medical reasons unless authorized by the Secretary of Health and Human Services. Many physicians seem to be unconcerned with this code as human growth hormones are frequently administered to those with no medical reason for taking them.

Distributors of this drug are also putting themselves at legal risk as well. Promoting its anti-aging benefits, distributors are targeting older consumers. These older consumers sometimes are willing to pay tens of thousands of dollars annually, a cost not covered by health insurance, to reap these benefits. Though its anti-aging effects have yet to be proven, distributors are profiting in this industry, which is estimated to be worth billions of dollars.

Demographics and Risks

For each population of patients receiving human growth hormone therapy, the risks involved differ. For children, for instance, benign intracranial hypertension development is a risk (with an occurrence rate of about 0.001), where as adults and elderly rarely develop this disease when using human growth hormones. Adults who receive the hormones, due to the misuse of the drug, are at risk for diabetes, carpal tunnel syndrome, fluid retention, joint and muscle pain, and high blood pressure. Their risk to benefit ratio is increased by the fact that definite positive results from the medication have not yet been proven in this population and their benefits are much less relevant. For children who require the medication for health related reasons, the risk to benefit ratio will always be lower than for other patients, specifically adults and elderly patients.

Medical Side Effects

Though the drug has positive effects on patients when used appropriately, there are also both serious and minor side effects associated with human growth hormone therapy. Some side effects that have been found to be associated with human growth hormone therapy include: peripheral edema, arthralgias, myalgias, back pain, paresthesias, carpel tunnel syndrome, headache, hypertension, rhinitis, and flulike symptoms. Many of these side effects appear to be dose related and are decreased with the lowering of medication dosage.

Treatment with somatropin may decrease insulin sensitivity, making it necessary for patients being treated to monitor glucose levels periodically. Glucose intolerance has been reported by human growth hormone patient recipients also suffering from a critical illness as well as elderly patients. This is much less of a risk for otherwise healthy children and adults. Data about diabetes as a concern for those receiving growth hormone therapy tends to be conflicting. One particular review, for instance, of large databases containing more than 35,000 patients on growth hormones indicated no greater incidence of type 1 diabetes than their age-matched counterparts. On the other hand, a recent study of an increased incidence of type 2 diabetes in children undergoing growth hormone therapy with risk factors for diabetes suggests that growth hormones may cause earlier expression of this condition.

Long Term Risks

Some of the risks involved in human growth hormone therapy, particularly the long term risks are currently being studied. Recent data indicate that increased levels of human growth hormone treatments may be related to an increased risk for the later development of prostate cancer. This potential risk is currently being looked into in population-based case-control studies.

Another long term concern being watched closely is the risk of cardiac enlargement. In short-term studies, it has shown that this has no short term effects on patients, but the long term risks are yet to be fully understood. Long-term surveillance plans for late-onset side effects are essential and are an important part of keeping this drug safe for patients.

Decreasing and Avoiding Risk

Compared to many pharmaceuticals, the risks involved are fairly low. To test the safety of recombinant DNA, the following must be considered: The vector should be well characterized and free from harmful sequences, limited in size as much as possible to the DNA required to perform the desired function, and it should not transfer any resistance markers to microorganisms not known to acquire them naturally. These factors all must be carefully considered and measured to prevent and limit risks in microbial biotechnology. This can be costly, which contributes to some of the high costs of this drug, but they are a necessary part of creating safe human growth hormones using microbial biotechnology.

Controversial Topics

Medical Challenges

A growing and challenging debate in the area of human growth hormone therapy is the diagnostic criteria for those with the need to be treated with growth hormones. Human growth hormone therapy is not only effective for patients with classic growth hormone deficiency, but for many other patients as well. Girls with Turner’s syndrome and children with idiopathic short stature respond to growth hormone treatment. Children who are particularly short in height due to genetics have shown to have increased heights when receiving human growth hormones as well.

Because this drug is so effective for so many, physicians are given the task of assigning growth hormones to individuals who do not fill the criteria for classic growth hormone deficiency at their own discretion. In many cases, certain patients will be administered human growth hormone therapy when seeing one physician while another might heavily discourage treatment. Due to the fact that there will always be an overlap between normal children, those with growth hormone deficiency, and those with other medical conditions and that all physicians possess their own ideology, there becomes a definite and not yet established need for an analysis and agreed upon set of standards for physicians to reference when prescribing this medication.

Ethical and Societal Concerns

An ethical concern connected to human growth hormone therapy is the physiological and psychological side effects for children receiving this medication. Years of injections have negative effects on the patients, similar to that of diabetic patients. One fear has been that injections may actually serve to enhance the negative self-image and stigmatization that already exist for many children with human growth deficiency. Some feel that human growth hormone therapy is not a viable solution. Many advocate that short stature, if it does not interfere with an individual’s ability to function appropriately, should not be treated as if it were a disease. These advocates feel that the use of growth hormones has merely increased society’s view that people should be of a particular height; they emphasize that a more proper solution is to work toward decreasing society’s negative image of short stature through education and less use of drugs such as human growth hormones.

After exploring the history of the development of this drug, it is interesting to consider what future developments and implications are possible. Although scientists have proven their abilities, it must also be understood that no matter the capabilities of scientists or the resources available, society as a whole has the ability to place limits on the development of this technology. The societal limit of a particular technology is defined as what society is prepared to accept being offered to it. If society is not prepared to grasp changes, changes will not come about, and progress will not be made. Ethical concerns may play a large part in society’s decision about what is accepting of. Other factors include social fears, the industry, the way the government presents the technology, and the media. Society being unwilling to accept developments in human growth hormones may eventually have an impact on restricted development. As of now, however, society seems to be accepting of improvements made in the production of human growth hormones. It is important to recognize, however, that many of the misuses which are due to the use of microbial biotechnology improvements will lead some to be skeptical of further developing this medication. Another factor involved is that many feel that human growth hormones are overused and are not “the answer” to short stature, may cause many to want to restrict progress with this medication.

Economic Matters

Unfortunately, those in need of this drug are burdened by the recent cost increases in medical care and prescription drugs. These trends have had an enormous impact on all prescription medication, but human growth hormone patients are feeling the effects even more so. The human growth hormone is a high-profile, small market medication. This makes it very expensive for the population in need in comparison to medications that are low-profile, large market pharmaceuticals. Human growth hormones can cost up to $18,000 to $30,000 per year of treatment. Beneficence is the ethical principle establishing the need to “do good.” With such high costs, making the product unavailable to many, this bioethical principle is being violated. This results in need for a change in the process by which this hormone is made or enormous changes in healthcare as a whole.

Because costs are so high, a very important social justice is violated and that is the unfair administration of the medication. There are many children with severe growth retardation who are unable to receive human growth hormone therapy because their parent or guardian’s income will not permit it. On the other end of the spectrum, there are adults and elderly who can afford the high cost of this medication. Though, they require it much less than other patients, they receive treatments. Many children who have a general short stature, most likely due to genetics, may be receiving human growth hormone therapy when a child with an improper functioning pituitary gland, because of family income, is not receiving therapy.

An improvement in the technology has increased the supply of this drug, something that would certainly lower prices. On the other hand, consumers demanding the drug for unnecessary purposes shifts the demand curve, making the drug less attainable for lower income children by increasing the price. Unfavorable distribution of the drug based on economics is a topic worthy of concern.

More about HGH

Searching for the Fountain of Youth? Dr. Mike Magee 11/1/2006 http://www.youtube.com/watch?v=27cs5zs0Ntc&mode=related&search=

Growth Hormone http://www.youtube.com/watch?v=3xvFyo7sZjc

References

• Berlin, C. (1997) Considerations related to the use of recombinant human growth hormones in children. Pediatrics (99)1, 122-129.

• Blanchard, M. (2004). Pause before writing that prescription: physicians jumping on the growth hormone wagon should consider serious liability risks. Cosmetic Surgery Times (7)14, 24.

• Committee on Drugs and Committee on Bioethics. (1999). Considerations Related to the Use of Recombinant Human Growth Hormone in Children. Pediatrics (99)1, 122-129.

• Conrad, P., & Potter, D. (2004). Human growth hormone and the temptations of biomedical enhancement. Sociology of Health & Illness (26), 184.

• Cook, D., Owens, G., & Jacobs, M. (2004). Human Growth Hormone Treatment in Adults: Balancing Economics and Ethics. The American Journal of Managed Care, S417-S419.

• Microbial Biotechnology. United States Department of Agriculture: Cooperative State Research, Education, and Extension Service. September 6, 2006 <http://www.csrees.usda.gov/nea/biotech/in_focus/biotechnology_if_microbial.html>

• NCBI: National Center for Biology Information

hGH-N HGNC:4261 GeneID: 2688 updated 03-Dec2006 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=DisplayFiltered&DB=gene

• Massachusetts General Hospital Last reviewed by David Juan,January 2006 MDhttp://healthgate.partners.org/browsing/LearningCenter.asp?fileName=96790.xml&title=

• McNerney, T., Watson, S., Sim, J., & Bridenbaugh, R. (1996) Separation of recombinant human growth hormone from Escherichia coli cell pellet extract capillary zone electrophoresis. Journal of Chromatography (A)744, 223-229.

• Root, A., Kemp, S., and Rundle, A. (1998) Effect of long-term recombinant growth hormone therapy in children--the National Cooperative Growth Study. Journal of Pediatric Endocrinology & Metabolism (11)1, 403-412.

• Salomon, F., Cuneo, R., Hesp, R., & Sonksen, P. (1989) The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. New England Journal of Medicine (321) 1797-1803.