Assignment 4: Journal Critique

Citation:
"Growth Hormone Deficient Patients After Traumatic Brain Injury - Baseline Characteristics and Benefits After Growth Hormone Replacement - An Analysis of the German KIMS Database." I. Kreitschmann-Andermahr, E.M. Poll, A. Reineke, J.M. Gilsbach, G. Brabant, M. Buchfelder, W. Faßbender, M. Faust, P.H Kann, and H. Wallaschofski. Growth Hormone and IGF Research. 18(2008) : 472-478.

Figure 1: The Main Causes of TBI and Head Injuries (click here to enlarge).

Figure 2: Pituitary Gland and Relationship to Hypothalamus

Introduction:

Growth hormone is necessary for many everyday bodily functions including, growth, metabolism, reproduction, etc. Therefore, it is important to ensure that you have sufficient growth hormone in the body at any given time. Many factors can influence the production and release of growth hormone, especially when the pituitary is affected, as it is the anterior pituitary where growth hormone is secreted. In recent evidence, it has been shown that patients suffering from traumatic brain injury (TBI) can suffer from growth hormone deficiency (GHD). This occurs due to hypothalamic-pituitary disturbances. Multiple studies have shown that the most frequent and common pituitary abnormality following TBI is a severe GHD.

Figure 3: Symptoms of TBI and Head Injuries (click here to enlarge).

Purpose:

The purpose of the paper being critiqued was to characterize adult TBI patients suffering from GHD and determine the effect of human growth hormone replacement in these patients. The patients were to be taken from the German Pfizer International Metabolic Database (KIMS). This database is an international pharmacoepidemiologic survey that is designed to monitor growth hormone replacement therapy in growth hormone deficient adults to ensure their safety.
Methods:

The KIMS database was searched for eligible patients for the study in question. These patients must have had perinatal head injury, head trauma and/or TBI. A total of 84 patients fit these circumstances out of a total of 2208 patients that were in the KIMS database at that time (October, 2006). All 84 patients, regardless of the specific head injury, were classified as having TBI due to the small sub-group populations. Each of the 84 TBI patients were matched with 84 GHD patients that were also in the KIMS database. However, their GHD was not due to TBI, but rather non-functioning pituitary adenoma (NFPA).

Figure 4: Pituitary Tumor in Brain (click here to enlarge)

"True naive" patients were classified as those whom had never before received human growth hormone replacement. "Semi-naive" patients were those whose human growth hormone replacement had stopped no less than six months prior to entry into the KIMS database, and finally, "non-naive" patients had continuous human growth hormone replacements before and after entry into the KIMS database.

The 84 patients whos GHD was due to TBI were divided into two groups: (1) the onset of GHD before the age of 18 and (2) the onset of GHD after the age of 18. At entry into the KIMS database, all patients were compared based on a variety of clinical characteristics, including height, weight, BMI, quality of life, etc. Serum IGF-1 levels were determined using radioimmunoassay. Serum concentrations of total cholesterol was also measured.

Data from all TBI patients that had at least a one year follow up after entry into KIMS was analyzed to view the effect of human growth hormone replacement therapy in TBI patients. These results were compared to the clinical characteristics obtained before entry into the KIMS database. As well, the results were compared to NFPA patients.

Results & Discussion:

There were no significant differences reported between patients having TBI and NFPA, except that TBI patients were generally younger at the onset of the pituitary disease, thus had a longer time period before being entered into the KIMS database. This may be because a higher number of childhood onset GHD patients receiving previous human growth hormone treatments in the TBI group in contrast to the NFPA group. The main difference between the two groups is that NFPA patients were observed to have additional ADH deficiency more frequently than TBI patients.

Figure 5: Pituitary Hormone Deficiencies Other Than GHD in TBI and NFPA Patients.

Patients with GHD onset during childhood were reported to be much shorter in height than GHD patients with adult onset. Following a one year follow-up in 61GHD TBI and NFPA patients, some notable changes were observed. The GH-dose, along with the IGF-1 SDS increased significantly. In NFPA patients only, a decrease was observed in LDL-cholesterol. Quality of life improved as well in both groups. Since a considerable amount of time had passed since the initial injury and the time of the study, this improvement cannot be caused only by the recovery process, but can be regarded as a treatment effect. This hypothesis was further validated in 2006, when a study published showed that TBI patients with growth hormone insufficiency showed a higher rate of depression and a lower quality of lift that did the TBI patients that did not portray growth hormone insufficiency.

Conclusion:

This evaluation of the German KIMS database portrays that TBI and NFPA patients with GHD have increased quality of life and other benefits from human growth hormone replacement therapy. As well, the shorter height of TBI patients with childhood onset GHD in combination with a postponed diagnosis and treatment results in shorter stature of the individuals. Although all 84 of these patients exhibited hypopituitarism, many victims of traumatic head injuries also suffer from this condition, and it sadly goes unnoticed.

Critique:

This paper was very clear, and its objectives were straightforward. The information provided was concise and pertained to the question at hand. I feel that the baseline characteristics at the beginning provided readers with a good idea of what the initial conditions were, before the human growth hormone replacement therapy. The purpose of the paper to provide an outlook of the effect of replacement therapy in TBI patients was proven to improve some aspects, including quality of life.

There were not many figures in the paper, however, the one that was provided did a phenomenal job at portraying the information clearly and concisely. The amount of information that was provided assisted in relaying the message, however, was not too complicated that it became confusing. The tables that were provided assisted in portraying statistics for the clinical characteristics, and were good at visually representing comparisons and contrasts between TBI and NFPA groups.

I do feel however, that the results would be more reliable had a bigger sample size been used, rather than 84. Also, I feel that the results may be somewhat inaccurate due to the fact that only patients from Germany were included in the study. There may be aspects of the gene pool that was used that would result in observations and conditions that may not occur worldwide, and in other areas. It is necessary in an experiment to try and cover all angles, rather than an isolated location. Overall, I feel the paper provided some interesting results and conclusions.

Future Experiments:

Future experiments for this study could include a larger sample size. Although 84 patients is a fairly big sample, the results would be more concrete if more patients were studied.

Also, regions other than Germany should be included in future studies. This can not only increase the sample size as previously mentioned, but also provide a wider range of genes.
Another study could pertain to the NFPA and the increase in ADH that was observed. The paper did not mention possible reasons for this, and it would be interesting to see the effects of this increase on body functions, as well as possible treatments.

The authors also suggest that future studies should be conducted to further determine the effect of human growth hormone in brain trauma patients with quality of life being the parameter in question.

References:
[1] Cocchi, D., Locatelli, V., Muller, E.E. (Eds.). (1993). Growth Homone and Somatomedins during Lifespan. Germany: Springer-Verlag.
[2] Daughaday, W.H., Harvey, S., Scanes, C.G., (1995). Growth Hormone. Florida, USA: CRC Press.
[3] Pang, P.K.T., Scanes, C.G., Schreibman, M.P. (1993). The Endocrinology of Growth, Development, and Metabolism in Vertebrates. San Diego, California: Academic Press, Inc.

Assignment #3: Function and Pathologies of Growth Hormone

Growth hormone is a peptide hormone that is synthesized in the anterior pituitary.

Functions:

Growth hormone has a variety of functions that are important in a vast range of species. Functions of growth hormone concern growth itself, metabolism, reproduction, immune responses, osmoregulation and more.

In mammals, growth hormone induces an increase in body weight and height (i.e growth). Growth hormone contributes to muscle growth by the combined effects of hyperplasia and hypertrophy. Hyperplasia is the process by which cell numbers increase by division and the prevention of cell death (apoptisis). Hypertrophy on the other hand is the increase in the size of cells.

Growth hormone also contributes to skeletal growth, by increasing calcuim retention, stimulating the division and multiplication of chondrocytes (cartilage cells) and increasing osteoblast (bone forming cell) activity.

Growth hormone has important effects (both direct and indirect) concerning carbohydrate, protein and lipid metabolism. Carbohydrate metabolism is affected by growth hormone in that it regulates the uptake of glucose by the liver, thus maintaining blood glucose within a certain range. Growth hormone also suppresses the actions of insulin to uptake glucose from the peripheral tissues. Protein metabolism is affected because growth hormone is a protein anabolic hormone, resulting in the increased uptake of amino acids, increased protein synthesis and decreased oxidation of proteins. Lipid (fat) metabolism relies on growth hormone because it exerts an overall lipolytic effect in which the hydrolysis of triglycerides form free fatty acids and glycerol.

Growth hormone has been termed a "cogonadotropin", and may serve a small role in both male and female reproduction. There is increasing evidence that GH can influence functioning of mammalian ovarian cells. As well, there is evidence that GH exerts a modulatory effect on reproduction in males. For example, in a study, GH was administered to preadolescent boys who progressed through puberty faster than the average male. These trends have not been confirmed for all species, nor all test subjects.

Growth hormone has been linked to the maintenance and control of the immune system. Growth hormone therapy to GH-deficient children appeared to enhance the ability of lymphocytes to proliferate.

The osmoregulatory function of GH can be seen due to the fact that renal function in mammals is affected by growth hormone. In a study reported in 1949, GH was found to have an increase on the glomular filtration rate and renal plasma flow.

Pathologies Relating to Growth Hormone:

There are many diseases associated with growth hormone excess and deficiency.

1)Acromegaly: acromegaly is the most common disease associated with excess production of growth hormone in adults. It results due to a tumor composed of somatotroph cells of the anterior pituitary. Eventually the tumor enlarges to a point that headaches and imparied vision occur due to pressure on the optic nerves. Symptoms of acromegaly include overgrowth of extremities, soft-tissue swelling, abnormalities in facial features (jaw and nose).

Figure 1: Acromegaly Disorder as it Progresses Through Time

2)Gigantism: Gigantism occurs as a result of excess growth hormone production in children or adolescents. It is usually a result from a tumor of somatotrophs. Robert Wadlow was a famous giant and when he died at the age of 22, he weighed 490 pounds and reached a height of 8 feet 11 inches.

Figure 2: Robert Wadlow: Gigantism

Treatment: Treatment for pituitary tumors causing acromegaly and gigantism include surgical removal of the tumor, focused radiation and a gowth hormone antagonist such as bromocriptine or octreotide.




3) Dwarfism: A result of GH deficiency in children results in dwarfism. Dwarfism is characterized by short stature and growth failure. In adults, GH deficiency is rare and results in deficiencies in strength, energy and bone mass. Causes are mutations of genes, congenital malformations involving the hypothalamus and/or pituitary gland. As well, damage to the pituitary from injury, surgery or disease can result in GH secretion problems.

Figure 3: Dwarfism Resulting from a GH Deficiency in a Child.

Treatment: Treatment of dwarfism involves the injection of recombinant GH from humans. In the past, GH extracted from human cadavres was used, however with modern technology, GH can be collected from recombinant DNA technology. It should also be noted that dwarfism in children cannot be reversed.

References:

[1] Cocchi, D., Locatelli, V., Muller, E.E. (Eds.). (1993). Growth Homone and Somatomedins during Lifespan. Germany: Springer-Verlag.

[2] Daughaday, W.H., Harvey, S., Scanes, C.G., (1995). Growth Hormone. Florida, USA: CRC Press.

[3] Muller, E.E., Pecile, A. (1975). Growth Hormone and Related Peptides. Amsterdam: Excerpta Medica

Assignment 2: Growth Hormone Structure

Growth hormone is a peptide hormone which is synthesized in the anterior pituitary gland. Its major structure is a single polypeptide chain, consisting of 191 amino acid residue (the number of residues vary slightly with growth hormone from different species). There are two disulfide bonds present in the growth hormone structure, located between Cys53 and Cys165. This particular structure has a molecular weight of 22, 124 daltons, or 22kD. Other isoforms of growth hormone consist of a 20kD version, and numerous dimers and polymers. The 22kD version however, accounts for approximately 70% of the growth hormone variants (Figure 1).

Figure 1: 2D Structure of Growth Hormone.

Sequence Alignment:

The sequence alignment for Cyprinus carpio (common carp), Oncorhynchus keta (chum salmon), and Carassius auratus (goldfish) was determined using Pubmed tools BLAST (basic local alignment search tool) and Clustal 2.0.8 Multiple Sequence Alignment.

BLAST locates regions of local similarity between sequences by comparing nucleotide or protein sequences to sequence databases and then calculates the statistical significance of matches. It can also be used to infer functional and evolutionary relationships between sequences. A scores table can be observed in the bottom of figure 2. This table gives numerical value to the degree of alignment between the species. Carp and Goldfish exhibited the highest score of 92, showing that they are very similar proteins. Carp and Salmon on the other hand, portrayed the lowest score of 62, showing that they are still quite similar. Goldfish and Salmon depicted a score of 67, again showing their similarity. The results from BLAST and Clustal 2.0.8 Multiple Sequence Alignment are portrayed in figure 2.

Figure 2: Alignment Results for Common Carp, Chum Salmon and Goldfish.

Key:

* Identical Residues

: Conserved Substitutions

. Semi-Conserved Substitutions

Figure 3 shows a phylogram of the alignment of the three study species. From this figure, it can be seen more clearly the relationship between the protein similarity of carp and goldfish, which are much more close than either are with salmon.

Figure 3: Phylogram Portraying the Similarity Between Three Species: Carp, Salmon and Goldfish.

References:

[1] Daughaday, W.H., Harvey, S., Scanes, C.G. (1995). Growth Hormone. Florida, USA: CRC Press.

[2] Pang, P.K.T., Scanes, C.G., Schreibman, M.P. (1993). The Endocrinology of Growth, Development, and Metabolism in Vertebrates. San Diego, California: Academic Press, Inc.

[3] Muller, E.E., Pecile, A. (1975). Growth Hormone and Related Peptides. Amsterdam: Excerpta Medica

Assignment 1

Growth Hormone

Growth hormone, is a peptide hormone that is synthesized in the anterior pituitary. In mammals, growth hormone promotes an increase in body weight and height, skeletal growth, muscle growth and increase in cell size and numbers. In rodents, it also accounts for increased tail length. Growth hormone induces growth in invertebrates as well as vertebrates. In humans, the presence of growth hormone is greatest immediately following birth, and during puberty at which times there is a high amount of rapid growth.

Figure 1: 3D Structure of Growth Hormone

Structure

Growth hormone is a single-chain polypeptide of 191 amino acids, and a molecular weight of approximately 22 kD in most species. Two disulfide bonds exist in the structure between Cys53 and Cys165, and between Cys182 and Cys189. There are many forms of growth hormone other than the 22kD version (which accounts for approximately 70% of variants). A 20kD version exists as well as numerous dimers and polymers.

Figure 2: Structure of Growth Hormone

Synthesis and Release

Growth hormone synthesis is affected by various factors including stress, exercise, nutrition, sleep etc. However, its primary controllers are growth hormone releasing hormone (GHRH), somatostatin (SS) and Ghrelin. GHRH stimulates both the synthesis and secretion of growth hormone, while somatostatin inhibits the release of GH. Ghrelin also stimulates GH release. The hypothalamus secretes GHRH, which acts on the pituitary, which releases GH. Ghrelin is released from the stomach, acts upon the pituitary, releasing GH. When the hypothalamus secretes somatostatin, it inhibits GHRH from acting upon the pituitary, as well, it inhibits the stomach from releasing ghrelin and the pituitary from releasing GH.

Growth hormone also stimulates the production of insulin-like growth factor 1 (IGF1) by the liver. Both GH and IGF1 are involved in a negative feedback loop together. High blood levels of IGF1 lead to decreased secretion of growth hormone, not only by directly supressing the somatotroph, but by also stimulating the release of somatostatin.

Figure 3: Control of Growth Hormone Secretion

Uses

Pharmaceutical and Biotechnological:

Uses involve growth hormone therapy in which GH is used to treat various medical conditions. In the past, GH collected and purified from cadavers was used to treat children with short stature. With modern technology, GH can be collected by recombinant DNA technology.

Another use of GH is for dairy cattle to enhance milk production. As well, it is used in raising pig to reduce fat deposition and enhance muscle growth.

Athletes sometimes use GH to enhance their athletic performance, as well as some people use GH to fight against the appearance of aging.

Disorders

Deficiency: In children, a GH deficiency results in growth failure, short stature and dwarfism. In adults, GH deficiency is rare, and is usually related to a problem in pituitary functioning.

Excess: An excess secretion of GH can result in two disorders.

Gigantism begins in young children or adolescents. It is a rare disorder and is usually caused by GH-secreting tumors located on the pituitary. Robert Wadlow was a famous giant, when he died at the age of 22, he weighed 490lbs. and reached a height of 8ft 11in.

Acromegaly is the second disorder associated with excess GH in adults who have pituitary tumors. Extreme growth of extremities (toes and fingers) along with the jaw are effects of the disorder.



















Figure 4: Robert Wadlow


References:
[1] Cocchi, D., Locatelli, V., Muller, E.E. (Eds.). (1993). Growth Homone and Somatomedins during Lifespan. Germany: Springer-Verlag.
[2] Daughaday, W.H., Harvey, S., Scanes, C.G., (1995). Growth Hormone. Florida, USA: CRC Press.
[3] Muller, E.E., Pecile, A. (1975). Growth Hormone and Related Peptides. Amsterdam: Excerpta Medica
[4] Strand, F.L. (1999). Neuropeptides: Regulators of Physiological Processes. London, England: The MIT Press