Acromegaly ( HUMAN PHYSIOLOGY 474)
I. Introduction
Normal growth in human beings is controlled primarily by hormones of the endocrine system. A major hormone in the stimulation of growth is a peptide hormone named accordingly as “Growth Hormone” or short-handedly as GH. It is secreted by the anterior pituitary gland through increased Growth Hormone Releasing Hormone (GHRH) secretion by the hypothalamus. As a result, increased GHRH secretion then stimulates increased GH secretion, which ultimately leads to increased Insulin-like Growth Factor 1 (IGF-1) secretion from target tissues such as the bones or muscle tissue, as well as the liver. The GH/ IGF-1 axis operates through, and is controlled by a negative feedback loop where increased secretion of IGF-1 leads to inhibition of GH secretion by the pituitary gland. Therefore, the hormone levels should remain within homeostatic range and should not lead to endocrine disorders. However, that is not always the case as hormone levels can diverge from this normal range due to a number of reasons. Among these reasons may be tumor formation in glandular tissues, inhibiting or stimulating drugs, receptor mutations, along with many other causes.
In cases of acromegaly, the GH/ IGF-1 axis is affected. There is a hypersecretion of GH after puberty, that causes an overall hypersecretion of IGF-1 in target tissues that cannot be controlled. This can cause the negative feedback loop to be compromised for varying reasons in each patient with this condition. However, Shlomo Melmed discusses the most prevalent cause of hypersecretion is due to an adenoma tumor surrounding the pituitary gland made of glandular tissue (1). Acromegaly can be determined by sampling blood hormone levels, but physical deformities are often present. Common physical abnormalities include enlarged hands, feet and facial structures. Other common symptoms include pain in the joints, fatigue, erectile dysfunction, oily skin, and vision disorder. Acromegaly is very similar to gigantism except for that it only occurs in adults after the epiphyseal plate has closed and no longer allows lengthening bone growth. Acromegaly is a chronic disorder affecting about 20,000 people a year in the U.S. according to Giustina, Mazziotti, and Canalis (2). While the disorder is not curable, it can be controlled through the use of hormonal therapy, medication, and removal of the adenoma if present in the patient. Most of the modern research is dedicated to finding new and alternative ways to treat patients with acromegaly in order to decrease mortality rates of patients with the disorder. Due to this focus in conducting research, the mortality rate of the disorder has decreased over time, but according to the study conducted by Dekkers et al., patients with the disorder are projected to have shorter life spans than healthy individuals due to the chronic effects, such as, the debilitating tolls it places on the skeletal system and liver over time (3). Patients with the noncancerous tumor surrounding the pituitary gland often receive radiation treatment or surgical removal of the tumor that lowers the hypersecretion of GH from the pituitary gland. However, this treatment is often accompanied by the use of hormonal therapy. Also, some cases of acromegaly are caused by mutations of IGF-1 receptors on the anterior pituitary gland that would not signal inhibition of GH, causing a hypersecretion to occur.
II. Overview of Patient Phenotype
The signs of acromegaly are enlargement of the feet, hand, face, and the extremities of the human body. Often, this is accompanied by an abnormally large tongue, bulging chest, and a deepened voice.
The symptoms are as a result of the hypersecretion of GH and overstimulation of bone growth. This includes overall fatigue and pain in the joints of the appendicular skeleton. The muscles also experience fatigue and the liver function can be affected due to its role in IGF-1 secretion. All of these signs and symptoms are a result of the pituitary glands hypersecretion of GH.
The biggest difference between acromegaly and gigantism is the age of onset. Gigantism typically occurs throughout childhood and continues throughout development and adulthood. While acromegaly can occur as early as late childhood or early adulthood after puberty, acromegaly is mostly diagnosed post-pubescent and leads to the signs of exaggerated extremity growth and development because the long bone epiphyseal plates have sealed and no longer allow for longitudinal growth. However, GH secretion does lead to increased osteoblast activity that is responsible for greater bone turnover and increased bone density which can also lead to physical abnormalities of skeletal bones such as in the misshapened or exaggerated jaw. Physical abnormalities typically worsen as time progresses and can only be reversed through plastic surgery.
Leontiou et al. conducted research in order to reveal the role of the aryl hydrocarbon receptor-interacting protein (AIP) gene mutation in causing cases of familial isolated pituitary adenomas (FIPA). AIP interacts with mechanisms involved in tumor suppression, so if mutation at the AIP gene loci occurs, tumors in the glandular tissue have an opportunity to proliferate and grow (4). The AIP gene is located on the long (q) arm of chromosome 11 at the position 13.3. This genetic link to acromegaly can be established through the findings such as this one, indicating mutations in certain genes can lead to endocrine disorders. While other genes and sporadic adenoma development may contribute to the random progression of acromegaly, understanding mechanistic pathways can lead to further research and successful treatment in the future.
III. Primary Defect
The primary defect for the cause of hormonal imbalance in patients with acromegaly is disruption in the homeostatic range of the GH/ IGF-1 axis. This is primarily due to hypersecretion of GH from the anterior pituitary gland. There are a few different ways this hypersecretion can occur and can vary in every patient. This is seen by a flaw somewhere in the negative feedback loop to recognize the imbalance or failure to adjust for the imbalance. There are multiple glands controlling the axis and vast amounts of target tissues in order to regulate this axis. However, understanding this axis must begin with setpoint and the integration center processing all of the hormonal balances in this case. The hypothalamus is located just below the thalamus in the brain. The hypothalamus functions to control autonomic responses and maintain homeostasis within the body. The hypothalamus releases many tropic hormones, but the focus in acromegaly is Growth Hormone-Releasing Hormone (GHRH). Dee Silverthorn outlines that GHRH is a 43-amino acid peptide that is secreted by the neurosecretory cells in the arcuate nucleus. This secretion then travels via the hypophyseal portal blood supply, through the pituitary stalk, and into the anterior pituitary lobe where it binds somatotrophs, the target tissue in the pituitary gland. Once it reached the somatotroph, GHRH binds to the GHRH receptor, that is a G protein coupled receptor made up of Gα, Gβ, and Gγ. Gα is the largest subunit and is the activated subunit that then activates adenylyl cyclase (AC). Once AC is activated, it catalyzes ATP into cAMP. This catalyzation then leads to activation of the enzyme protein kinase A (PKA). Finally, at the end of this cascade, Ca2+ channels open and depolarization causes GH to be secreted by the somatotroph (5).
In order to balance this secretion from the pituitary gland, the process can be inhibited by a tropic hormone also released by the hypothalamus. Cells in the periventricular region release the hormone somatostatin (SS), which acts as an inhibitor of GH secretion in the anterior pituitary lobe. Once SS is secreted from the hypothalamus, it travels through the pituitary stalk and normally binds to the SS receptor also on the somatotroph. The SS receptor is an inhibitory G protein coupled receptor, whereas the GHRH is a stimulating G protein coupled receptor. The binding of SS to the SS receptor causes the Gα subunit to inhibit adenylyl cyclase from catalyzing ATP to cAMP, therefore inhibiting the secretion of GH. Understanding both the stimulating and inhibiting pathways of GH are imperative into understanding how acromegaly occurs at the biochemical and molecular level.
In patients with acromegaly, it is possible for mutations to occur in the SS receptors of somatotrophs, leaving the inhibitory pathway of GH ineffective. This ineffectiveness would lead to little or no regulation or control of GH secretion. This can be the main defect in acromegaly patients that are diagnosed with the non-cancerous adenoma from glandular tissue. This defect alters the whole negative feedback loop that is normally involved in maintaining proper GH concentrations. The hypersecretion of GH poses a threat to the body tissues, but only through the effects of GH on the release of IGF-1 in the target tissues. For this reason, acromegaly is closely associated with the tell-tale signs that are present to some degree in every case. Among these tell-tale signs are the exaggerated hands, feet, fingers, toes, and skull.
IV. Secondary Issues
In a normally functioning individual, when GH is being hypersecreted, the negative feedback loop would prevent further excessive GH secretion. This is accomplished by GH stimulating secretion of IGF-1 from peripheral target tissue. Then, IGF-1 directly inhibits GH secretion by suppressing the somatotrophs. Furthermore, IGF-1 stimulation can indirectly inhibit GH secretion by suppressing GHRH release in the hypothalamus. The two inhibitory pathways being discussed are called the short negative feedback loop and long negative feedback loop, respectively. IGF-1 can also indirectly inhibit GH secretion by stimulating somatostatin release in the hypothalamus, which directly inhibits GH release in the anterior pituitary. However, in patients with acromegaly, this inhibitory pathway renders useless due to either mutation in SS receptors or up-regulation of the GH receptors, causing flooding of the GH release. IGF-1 can no longer inhibit the hypersecretion of GH and homeostasis is interrupted, causing more IGF-1 to be secreted and utilized in the target tissues in the body. This leads to the signs and symptoms of the disease that are not normally present in a healthy individual with a fully functioning endocrine system.
GH has both acute and chronic effects on the human body. Field, Spiller, and Gordon investigate the acute effects of GH and it’s diabetogenic actions like stimulating lipolysis in the bodies adipose tissue, inhibiting glucose uptake by the muscular system, and inhibiting gluconeogenesis within the liver (6). In acromegaly, the acute effects are not a factor, because the disorder is a chronic condition. However, the acute effects lead to the chronic effects because of the inability to return to homeostatic range. The chronic effects of GH are promoting tissue growth and causing hypoglycemia through hypersecretion of IGF-1 in target tissues. The target tissues are primarily the liver, muscles, kidneys, bones, and cartilage. The physical growth in acromegaly patients is a firm marker that there is a hormonal imbalance, but are typically not life threatening and can be corrected to a degree through plastic surgery. The chronic effect of hypoglycemia is not as mild of an issue.
Hypersecretion of GH causes inhibition of gluconeogenesis in the kidneys and liver tissue. This can result in hypoglycemia because the body tissues are not receiving glucose at the concentration needed to maintain normal function. Muscles cannot function properly with decreased glucose transport because glucose is the primary fuel for aerobic respiration and energy output for movement. If this persists without intervention, the individual will eventually die due to hypoglycemia as would a person with diabetes that injects too much insulin or a normal individual that suffers from starvation. Of course all of these scenarios decrease blood glucose levels to unsafe concentrations, and if unattended or severe enough, seizures, unconsciousness, and eventually death may occur. Therefore, it is very important to intervene with the effects of acromegaly and control the hypersecretion of GH. Luckily, most modern research focused on acromegaly is invested in restoring normal pituitary function and balancing the hormonal concentrations within the body so hypoglycemia is not a chronic condition as it was in the past.
V. Intervention
Intervention techniques for acromegaly include three main treatment options. First, hormonal treatments are being researched and can be used as a substitute for an inhibiting hormone on GH hypersecretion. There are many hormones being tested and a few are showing very promising results for chronic treatment of the disorder. Second, radiation is an intervention technique in cases where the adenoma is present surrounding the pituitary gland. Research is being conducted to record its effect on tumor shrinkage and inhibiting metastasis. However, radiation is usually ineffective without surgery to remove the shrunken tumor. It is primarily used as a short term treatment option. Third, transsphenoidal surgery is being explored in order to remove the tumor after radiation treatment has ended. This technique is not preferred as it is a very high risk and is a difficult procedure to perform due to location within the skull and structures surrounding the pituitary gland. Often, after the tumor is removed, it begins to form again as not all cancerous tissue is collected, posing major issues. The greatest hope for a cure is in hormonal therapy and ways to make it more affordable to the patient. To date, acromegaly remains incurable and can only be managed through the techniques discussed above.
Colao et al. conducted an experiment to assess the pretreatment of octreotide (OCT) for three to six months in acromegaly patients before the transsphenoidal surgery was performed in the experimental group. The untreated control group consisted of acromegaly patients that did not receive OCT treatment. The purpose of this study was to examine the clinical effects of the OCT treatment before the patients underwent surgical procedures to remove the pituitary adenoma. The results showed many reductions in clinical signs such as blood glucose levels, blood pressure, blood lipid levels, as well as GH levels in the experimental group. Also, reduction of tumor size was reported in five of the twenty-two treated patients (7). This research shows promise for an alternative to surgery and radiation, since the GH levels fell and other clinical signs did too.
There are other hormones being tested that act as GH inhibitors to make up for the lack of somatostatin being secreted to control the hypersecretion. Petersenn et al. conducted research testing the efficacy of a different hormone than OCT. Pasireotide (SOM230) is a multi-receptor ligand somatostatin analog with affinity for somatostatin receptor subtypes similar to those of GH secreting pituitary adenomas. This indicates that pasireotide could possibly be used to evoke a biochemical response in patients and be a therapy option for reducing tumor growth. The study found that thirty-nine percent of patients saw a twenty percent or greater reduction in tumor size (8). In general, the receptiveness for the ligand was fairly high in the patients, further opening doors to possibilities in the future for acromegaly treatment.
With all the different hormonal options being tested and the results being hopeful, search for the therapeutic treatment with the greatest efficacy is in the cross-hairs. Hormone therapy is beneficial because it not only acts to fix the primary defect, but also improves the symptoms of the disorder. Andries et al. found that in a randomized crossover study testing two different hormonal treatment options, the effectiveness of lanreotide Autogel (LAN) and octreotide long-acting repeatable (OCT-LAR) were dependent upon the patient and were a mix of reactions. Since it was a crossover study, the ten patients completed six months of either treatment modality, then switched to a remaining six months of the other. The study concluded that while varying efficacies were examined, general biochemical responses were received by the patients for both treatments. However, six out of the ten patients reported different side-effects for each modality (9). The significance of the study reports that if a patient isn’t responding well to either treatment, switching the patient to the other may increase responsiveness or reduce side-effects. This study dives deeper into the use of somatostatin analogues to treat patients suffering from acromegaly effectively.
Radiation and surgical procedures are short term treatment options and typically result moderate relief of symptoms. The long term treatment is through hormone therapy, given for the remainder of the patient’s life. However through hormone therapy, a patient can live a somewhat normal and active life, except with many more bothersome doctor appointments and tests. Typically, the hormone concentrations of GH and IGF-1 are measured together and are important in checking if the patient is producing too much of either hormone, according to Brzana et al. (10). If the homeostasis is interrupted again, the doctor could order a new prescription of a different hormone therapy. Overall, the lifestyle of an individual with acromegaly is not severely affected if proper treatment is administered.
VI. Future Directions
Technology is rapidly evolving and becoming cheaper, more advanced, and more functional. This is especially seen in development of tools in medicine. For instance, radiation machines are not what they used to be even twenty years ago. In the 1980’s, radiation treatment was very strong and affected parts of the body that did not require radiation, causing complications in healthy tissue. Today, radiation treatment is literally pinpointed and controlled to the target tissue. If progress continues, we may see a drastic change in the effectiveness of radiation treatment completely destroying cancer tissue irrelevant of the location in the body, like in the brain for acromegaly patients. Holdaway, Bolland, and Gamble researched the effect of lowering GH and IGF-1 serum levels on patient mortality and found that treatment significantly increases survival rates in patients with acromegaly (11). In addition, surgical instruments and procedures are evolving everyday. Procedures are becoming less invasive as technology advances, leading to possibilities of safer adenoma removal from the pituitary gland. Sleight of hand may no longer be an issue in operating rooms with the assistance of machines and precise instruments being invented.
Regarding hormonal therapy, time and research are the largest variables controlling the advancement in this field. Effective research takes time and must be performed in order to correctly assess the efficacy of new hormonal substitutes. An emerging field is synthetic hormones derived from stem cells, but manipulated to cater to the function desired within the body. If scientists can harness and perfect this technology, most endocrine disorders could be cured since endocrine disorders primarily exist due to hormonal variance. The possibilities are endless with the ever-expanding technology field and its absorption into the medical field. Hopefully one day acromegaly is treated at first signs of the disorder and will no longer affect the lives of those suffering from it.
VII. References Cited
1. Melmed, Shlomo. 2009. “Acromegaly Pathogenesis and Treatment.” The Journal of Clinical Investigation 119(11): 3189.
2. Giustina, A., Mazziotti, G., and Canalis, E. 2008. “Growth hormone, insulin-like growth factors, and the skeleton.” Endocrine Reviews 29(5): 535–559.
3. Dekkers, O.M., Biermasz, N.R., Pereira, A.M., Romijn, J.A., and Vandenbroucke, J.P. 2008. “Mortality in Acromegaly: A Meta-analysis.” The Journal of Clinical Endocrinology & Metabolism 93(1): 61–67.
4 .Leontiou, C.A., Gueorguiev, M., Van der Spuy, J., Quinton, R., Lolli, F., Hassan, S., Chahal, H.S., et al. 2008. “The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas.” The Journal of Clinical Endocrinology & Metabolism 93(6): 2390–2401.
5. Silverthorn, D. 2013. “Introduction into the Endocrine System.” Human Physiology. 6ed. 219–228.
6. Field, J., Spiller, K.L., and Gordon, M.B. 2015. “THR-427: Management of Hyperglycemia in a Patient with Acromegaly Treated with Pasireotide LAR: A Case Study.” Endocrine Society.
7. Colao, A., Ferone, D., Cappabianca,P., Laura del Basso De Caro, M., Marzullo, P., Monticelli, A., Alfieri, A., Merola, B., Call, A., Divitiis, E., Lombardi, G. 2013. “Effect of Octreotide Pretreatment on Surgical Outcome in Acromegaly.” The Journal of Clinical Endocrinology & Metabolism.
8. Petersenn, S., Schopohl, J., Barkan, A., Mohideen, P., Colao, A., Abs, R., Buchelt A., Ho. Y., Hu, K., Farrall A., Melmed, S., Biller, B. 2013. “Pasireotide (SOM230) demonstrates efficacy and safety in patients with acromegaly: a randomized, multicenter, phase II trial.” Endocrine Society.
9. Andries, M., Glintborg, D., Kvistborg, A., Hagen, C., and Andersen, M. 2008. “A 12‐month randomized crossover study on the effects of Lanreotide Autogel and Octreotide long‐acting repeatable on GH and IGF‐l in patients with acromegaly.” Clinical Endocrinology 68(3): 473–480.
10. Brzana, J.A., Yedinak, C.G., Delashaw, J.B., Gultelkin, H.S., Cook, D., and Fleseriu, M. 2012. “Discordant growth hormone and IGF-1 levels post pituitary surgery in patients with acromegaly naïve to medical therapy and radiation: what to follow, GH or IGF-1 values?.” Pituitary 15(4): 562–570.
11. Holdaway, I.M., Bolland, M.J., and Gamble, G.D. 2008. “A Meta-analysis of the Effect of Lowering Serum Levels of GH and IGF-I on Mortality in Acromegaly.” European Journal of Endocrinology 159(2): 89–95.
12. Cook, David. 2012. “Acromegaly Patient”. Hormone Health Network. Digital Image.
13. Mary Ann Emanuele, Frederick Wezeman, and Nicholas V. Emanuele. 2003. “Growth Hormone Axis”. The Journal of the National Institute on Alcohol Abuse and Alcoholism 27(1): Digital Image