Where Does Growth Hormone Come From?
Growth hormone is a small protein produced by the pituitary gland, a small dime-sized gland that extends from the base of the center of the brain located right behind the eyes.  In addition to growth hormone, the pituitary gland also produces a number of other important hormones as well, such as prolactin, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, adrenocorticotropic hormone, oxytocin, and vasopressin.  The part of the brain just above the pituitary called the hypothalamus produces two hormones called growth-hormone-releasing hormone and somatostatin that plays an important role in controlling the amount of growth hormone released by the pituitary.

The amount of growth hormone released by the pituitary over our lifetime changes with increased amounts released during childhood, especially during the pubertal growth spurts, and decreasing amounts, as we get older.

When growth hormone is produced by the pituitary gland, it is released into the bloodstream that then stimulates the liver primarily to release another hormone called insulin-like growth factor-I or simply known as IGF-I. IGF-I can be measured in blood by taking a blood sample. As IGF-I levels do not fluctuate greatly throughout the day for an individual person as much as growth hormone, IGF-I is used by physicians as a screening test to assess for growth hormone deficiency or excess in conditions such as acromegaly and gigantism.  Both growth hormone and IGF-I acts on many tissues in the body, including brain, bone, fat and muscles.

What Does Growth Hormone Do?
Growth hormone functions to regulate body composition, body fluids, muscle and bone growth, mental function, and possibly heart function.  On the other hand, deficiency of growth hormone in children is easy to recognize with poor growth hormone. In adults, growth hormone deficiency is not so easy to detect since adults have achieved adult height after their bones have fused, thereby preventing further growth.  The deficiency of growth hormone in adults can be most appreciated by assessing the body composition. These important parts of our bodies are not nurtured properly in growth hormone deficiency, resulting in an abnormal metabolism.  With this deficiency, fat tends to be deposited more easily, especially around the central part of the abdomen.  Since growth hormone can affect muscles, they also change for the worse, which means there is less muscle strength and less ability to exercise.  Bones, too, are affected by becoming weaker with low bone mineral density, increasing the risk of osteoporosis as we get older. This combination of more fat, less muscle and less bone mineral density represents the abnormal body composition changes as the result of growth hormone deficiency affecting adults. 

Adults with growth hormone deficiency also experience adverse effects on cholesterol and glucose metabolism.  These changes result in a higher overall cholesterol level in blood, which is undesirable.  The “good” cholesterol also changes.  We want this “good” cholesterol level to be as high as possible.  This good cholesterol (also referred to as HDL cholesterol) changes to a lower level as the result of growth hormone deficiency.  In addition, because of the increased risk central fat deposition associated with adult growth hormone deficiency, the risk of developing diabetes and cardiovascular disease increases as well when they get older.  

What Are Some Symptoms of Growth Hormone Deficiency in Adults?
Adults who develop growth hormone deficiency may report central weight gain, difficulty to lose weight, dry skin, fatigue, and often do not feel their usual selves.  Most notice a decrease in their physical energy level and endurance for exercise. Some may avoid social contact or avoid socialization with their friends and family members, and may develop anxiety and depression. Other people with growth hormone deficiency think they feel normal, but do not remember the way they felt before they developed the growth hormone deficiency. These people may derive  improvement in how they feel and energy levels after starting on growth hormone therapy.

Causes of Growth Hormone Deficiency in Adults
Most children who develop growth hormone deficiency do so because the hypothalamus, for unknown reasons, fails to function and does not produce sufficient amounts of growth-hormone-releasing hormone to stimulate the pituitary gland to release growth hormone.  There may not be a visible cause of pituitary damage on MRI in most children with growth hormone deficiency. This deficiency may continue into adulthood. Adults, however, who develop growth hormone deficiency usually do so because of some damage to the pituitary gland and hypothalamus. This damage results in an inability of the pituitary gland to make growth hormone in sufficient amounts needed by the body. The most common cause of pituitary and hypothalamus damage in adults is a tumor in the pituitary gland and hypothalamus. Either the tumor itself, or the treatment in the form of surgery to remove the tumor or radiation therapy of the tumor can cause adult growth hormone deficiency. Other recently described conditions that can cause adult growth hormone deficiency include head injury, stroke, bleeding in the base of the brain and infections to the brain, such as meningitis. Some adults may also have persistent under-active hypothalamic drive (activity) as a cause of growth hormone deficiency similar to the most common reason for children to develop growth hormone deficiency, but this is rare.

What Methods Are Used to Detect and Confirm Growth Hormone Deficiency?
Your doctor will choose an appropriate test to detect and confirm if you have growth hormone deficiency or not.  Since measuring growth hormone in the blood is hard to interpret because growth hormone secretion fluctuates throughput the day and often can be low in normal individuals, a low level in blood does not confirm growth hormone deficiency.  Your doctor will choose a stimulation test that is appropriate for you that will stimulate growth hormone secretion from your pituitary gland into your bloodstream. By measuring your blood at intervals after administration of a medication to stimulate GH secretion, your responses to the stimulus can be obtained by measuring several growth hormone levels in the blood. In normal individuals there is a rise in blood growth hormone levels after the stimulus but in deficient individuals, there is either no rise, or a minimal rise, which will then confirm that you are growth hormone deficient.  The commonly used medications to stimulate growth hormone secretion include insulin and glucagon. The insulin tolerance test is considered the reference standard growth hormone stimulation test but the test is labor intensive, can cause severe hypoglycemia, and is contraindicated in certain patients. The glucagon test is considered the alternative test if the insulin tolerance test cannot be performed in certain patients. In December 2017, the United Stated Food and Drug Administration approved the use of a medication called Macrelin, which can be taken by mouth, as the test that can be used to test for adult growth hormone deficiency by measuring GH levels after an oral dosing.

All of these growth hormone stimulation tests requires you to be fasted. On the day of the test, an IV line will be placed in your arm for multiple blood draws to measure your growth hormone levels. Your doctor will choose one of these that best fits your situation.

How is Growth Therapy Administered?
Growth hormone is administered daily by injection underneath the skin into fat tissue. Most individuals give it to themselves in the fat in the lower abdomen. Previously, needles and syringes were used that is similar to those used by diabetic patients. Nowadays, many easy-to-use pen delivery devices are available to administer growth hormone more reliably and some pen devices can hide the needle so well that you cannot even see it when you are giving the injection.  You will need a special “sharps container” for disposal of the needles.  Your doctor will calculate the dose of growth hormone appropriate for you. The dose may change depending upon your responses and blood tests taken to monitor therapy. It is important to note that growth hormone cannot be administered orally because it is digested in the stomach before it can be absorbed into the bloodstream. 

What Symptoms Suggest Taking Too Much Growth Hormone?
If you are receiving too much growth hormone, you may develop side-effects such as swelling of the ankles, aching in your joints, pain in your hands or rise in blood glucose and blood pressure. If these symptoms do occur, you should notify your doctor immediately. Usually side-effects subside when your dose of growth hormone is decreased or the treatment is stopped temporarily. Once the side-effects have resolved after stopping treatment, you can discuss with your physician to see if you can resume at a lower dose. It is important to note that not every patient feels better immediately being on growth hormone treatment, which is why you should be on growth hormone for at least twelve to eighteen months. During that time, your doctor will slowly adjust the dose of growth hormone that is right for you. 

Summary
Adults need growth hormone all of our lives, not only as children for growth purposes.  Without growth hormone as adults, there is an increased risk of developing abnormal body composition, increased central fat deposition, increased risk of cardiovascular disease and diabetes, increased risk of low bone mineral density, and reduced physical and psychological energy and well-being. Growth hormone replacement in adults with growth hormone deficiency often improves most, but not all, symptoms associated with this condition, and should be continued lifelong, if possible.

The Transition from Child to Adult with Growth Hormone Deficiency

Growth Hormone Therapy
Growth hormone (somatotropin), a principal stimulator of body growth, is produced by the pituitary (or master) gland, a small glandular structure located at the base of the brain. Insufficient production of growth hormone in children causes slow growth. Because growth hormone deficiency produces striking effects in children, it has been a recognized condition for many years. We usually associate the term growth hormone deficiency with children and with the process of statural growth. Growth hormone, however, is also secreted in adult life, and adults need GH to maintain health. Adults who produce insufficient growth hormone can be called as having adult growth hormone deficiency.

Causes of Growth Hormone Deficiency
Growth hormone deficiency in some adults is due to the continuation of a process that began in infancy or childhood, or it may occur during adulthood. The most common form of growth hormone deficiency beginning early in life is termed "idiopathic", meaning that the cause is not known. Known causes beginning in childhood include developmental defects in the region of the pituitary gland, genetic abnormalities with the production of growth hormone, damage to the pituitary area resulting from tumor, surgery, irradiation, etc. The most common causes of adult-onset growth hormone deficiency are tumors in and around the pituitary gland and hypothalamus. Such tumors may compress and damage the remaining pituitary gland, and growth hormone deficiency may follow after surgery is performed to remove the tumor. Other causes of damage to the pituitary gland in adults include brain irradiation, infection, bleeding in the skull base, bleeding into the tumor and head injury.           

The Adult Who Was Growth Hormone Deficiency During Childhood
In the many decades that growth hormone has been used as treatment, the emphasis has been on treating the short stature in GH deficient children. For the most part, these patients have been led to believe that the only purpose of growth hormone therapy was to promote growth so that they would achieve an acceptable adult height and that therapy would not be needed once their final adult height is reached. Experience, however, has led to the conclusion that a substantial number of adults who were GH-deficient during childhood need to continue GH therapy in adult life due to persistence of growth hormone deficiency.

Several findings have led to this conclusion:

• When growth hormone deficiency therapy is stopped, the young GH-deficient adult tends to gain weight and become relatively obese. This excess of body fat tends to accumulate around the abdomen.

• This relative deficiency of muscle mass results in diminished strength and physical performance, changes that may be manifested as decreased ability to perform tasks such as lifting heavy loads or to sustain physical tasks for long periods of time. Adults with growth hormone deficiency have impaired ability to consume oxygen and expend their body energy, both at rest and at work.

• Adults with growth hormone deficiency also may have lower mineral content in their bones, predisposing them to osteoporosis and fractures in their later years in adulthood. All of us lose bone mineral and have increased tendency to fracture our bones as we age, but this natural process may be accelerated with GHD. Additionally, if the growth hormone deficient adult had insufficient growth hormone during childhood when bones normally accumulate mineral, he/she is likely to begin adult life with low bone mineral content. This, superimposed on the loss of mineral during adulthood, eventually results in lower-than-normal bone mineral content and a greater predisposition to fractures.

• Blood lipid profiles in adults with growth hormone deficiency are such that they are likely to be predisposed to develop atherosclerosis in later years of adulthood. Their blood levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides are higher than individuals who have normal growth hormone secretion, suggesting that these findings are significant in contributing to the shorter lifespan seen in adults with hypopituitarism (growth hormone deficiency associated with deficiencies of other pituitary hormones). This is because, despite treatment of the thyroid, adrenal and gonadal hormones, the excess death rate is due mainly to cardiovascular problems.

• Young adults who were growth hormone deficient during childhood may have signs and symptoms of impaired physical and psychological well-being. These include feelings of depressed mood, emotional instability, social isolation, anxiety, low self-esteem and reduced vitality.

Treatment of the Growth Hormone Deficient Adult Who Had Growth Hormone Deficiency in Childhood
Although children who have growth hormone deficiency may continue to be growth hormone deficient in adulthood, the capacity of some patients to secrete growth hormone improves over time. Some patients, therefore, will not need growth hormone therapy in adult life. This is why it is very important that as each GH-deficient child that reaches adulthood, growth hormone treatment should be stopped for at least 1 month and re-testing with a GH stimulation test should be performed to determine the need for continuing therapy in adulthood. The extent and nature of testing needed for this purpose will vary from one patient to another. During this time, the patient may switch over from seeing a pediatrician to seeing an adult endocrinologist. This time is crucial for the pediatrician to prepare the patient to transition over his/her care to an adult endocrinologist.  

If treatment is needed in a patient with persistent GH deficiency in adulthood, a variety of beneficial effects can be anticipated:

Effects on Body Composition and Bone Mineral Content
Growth hormone therapy may decrease body fat, with the greatest reduction occurring in the abdomen. Concurrently, the reduced lean tissue mass is increased by treatment with growth hormone. This change is reflected in large part by improvement in muscle mass. The improvement in body composition may help in reducing the risk of developing future diabetes. Although improvements in bone mineral density would be an anticipated effect of growth hormone replacement therapy, systematic studies have not shown that this occurs. This may be because bone changes can take a long time to detect. Therefore, longer periods of observation are needed to assess changes in bone mineral density.

Effects on Physical Performance
Growth hormone therapy in adults has been shown to improve exercise performance, oxygen consumption and cardiac output that is likely to be due to its direct beneficial effects on skeletal and heart muscle.

Effects on Blood Lipids
Growth hormone therapy has been shown to improve blood lipid profile, especially when combined with a statin. Specifically, total cholesterol and low density (bad cholesterol) lipoprotein cholesterol are reduced. The extent to which these changes decrease the development of future atherosclerosis are not yet known.

Effects on Psychological Well-Being
One of the striking effects of growth hormone therapy in adults with growth hormone deficiency is the improvement in psychological well-being reported by these patients. Some, but not all, patients experience an improvement in their psychological well-being.  Improvements in mood and in the level of perceived psychological distress has also been documented. 

Other Considerations
Treatment with growth hormone requires that the hormone be injected daily into the fat tissue beneath the skin usually at bedtime. This is made relatively simple by the need for small volumes of growth hormone and the availability of fine, small-bore needles with a pen device. Over the years, research studies have shown that growth hormone therapy is relatively safe. Growth hormone therapy in adults, especially in low doses, has uncovered few adverse effects of the hormone. In adults who are treated with high doses of growth hormone, edema (collection of fluid in tissue) and discomfort in the joints are sometimes observed. Decreasing the dosage temporarily can relieve these. Because growth hormone antagonizes the action of insulin, high growth hormone doses can raise blood glucose levels. This has not proven to be a significant problem in adults particularly if blood glucose levels are monitored and lower growth hormone doses are used. Because growth hormone can cause tumors to grow, this raises the concern that long-term growth hormone treatment might promote the development of tumor growth. These concerns, however, have been unfounded as long-term follow-up studies in adults with growth hormone deficiency have not shown this to be the case. 

Summary:

• Adults still produce and need growth hormone. It is just that they do not need as much growth hormone as children.

• Adults who are deficient in growth hormone accumulate excess fat centrally, have decreased lean tissue, have lower bone mineral content, have an unfavorable blood lipid and glucose profile, and experience undesirable psychological effects.

• Treatment with growth hormone reverses/attenuates many of the effects of growth hormone deficiency, and may lead to better physical performance and a healthier psychological status.

• Use of growth hormone in adults and children for over 20 and 40 years, respectively, indicate that it has a high degree of safety.

Evaluation Process of Adults with Growth Hormone Deficiency

Introduction
You have been referred to an endocrinologist, a doctor who specializes in the diagnosis and treatment of disorders of the endocrine glands. Endocrine glands release chemicals into the blood in a complex manner, which tell parts of the body to do certain jobs at certain times of the day. These chemicals are referred to as hormones. Endocrine disorders can be in the form of too little or too much hormones being produced. A deficiency exists when there is not enough of a hormone in the body. In order for your doctor to make an accurate diagnosis, testing may be necessary, and some of the testing can be quite complicated. This section was written to help you and your family understand the evaluation process of hormone deficiencies. 

Control of Hormones/Hormone Deficiency
The hypothalamus controls the pituitary gland; both are located in the brain. The pituitary gland releases or controls many hormones in the body. The hormones are released in very small amounts into the bloodstream and then travel to parts of the body (referred to as target organs) to perform a specific job. These hormones control many of the body's functions, which are the following: thyroid stimulating hormone (TSH) turns the thyroid gland "on" in order to control your metabolism, adrenocorticotrophic hormone (ACTH) stimulates adrenal cortisol production to assist your body in daily function and stress, vasopressin assists in the salt and water regulation of the body, gonadotropins (FSH, LH) stimulate the ovaries (in women) or testes (in men) to release "sex" hormones (estradiol or testosterone), and growth hormone (GH) that causes growth in children and affects fat metabolism, bone density, lipid metabolism, and muscle in children and adults. 

Deficiencies of these hormones may occur alone or in combination with one or more other hormone deficiencies. The hormone(s) deficiency may be congenital, resulting from a defect in the brain. The deficiency may also be acquired, stemming from the damage to the brain after a severe head injury, serious illness (such as meningitis or encephalitis), brain tumor and/or radiation. Sometimes no cause for the hormone deficiency can be identified.

Evaluation and Testing
In order to confirm or determine the possibility of hormone deficiencies your doctor will perform an examination and ask you some questions. Past records may have to be reviewed. Screening blood tests will usually be done. These blood tests will check the secretion of the pituitary hormones and their target organs.

Possible tests that may be done are listed:

• ACTH/cortisol/ACTH stimulation test (to test adrenal function)

• Free T4/TSH (to test thyroid function)

• FSH/LH and estradiol or testosterone (to test stimulation ability of the ovaries or testes)

• IGF-I/GH stimulation test (an indirect measure or screening test for growth hormone production)

• Electrolytes (measures water & salt balance) 

You may need to have a picture of the brain; this is done by an MRI scan (a CT is performed for those who have a pacemaker and cannot undergo an MRI scan).  These tests are not painful but you will have to hold still for approximately one hour during the test. 

Growth Hormone
If there is a possibility that you have GH deficiency, more testing will have to be performed. Growth hormone is secreted by the pituitary gland in quick bursts and does not last long in the blood, so checking a single blood sample for growth hormone will not be helpful. Deep sleep, vigorous exercise, and certain drugs are known to stimulate the secretion of growth hormone. The amount of GH in the blood is measured by taking blood samples over a period of time. This is done by performing a "GH stimulation test." This refers to drawing baseline hormone levels, stimulating GH release by giving a drug, drawing intermittent GH levels for one to four hours. The commonly used medications to stimulate GH secretion include insulin and glucagon. In December 2017, the United Stated Food and Drug Administration has approved the use of a medication called Macrelin, which can be taken by mouth, as the test that can be used to test for adult GH deficiency. All of these growth hormone stimulation tests requires you to be fasted. On the day of the test, an IV line will be placed in your arm for multiple blood draws to measure your growth hormone levels.

Your doctor will determine the specifics of the tests, such as type of drug, length of test, and amount of the samples. 

Once the diagnosis of adult GH deficiency is confirmed, your doctor will need to make sure you are on adequate hormone replacement for other hormone deficiencies prior to stimulation testing. You will be given instructions. You should not have anything to eat or drink, except for water, after midnight the night before the test. You should have minimal activity before the test (no exercise that morning). An indwelling IV will be started and baseline hormone levels will be drawn. You will be given a medication. Your doctor or nurse will review your medications, the medication to be used and its effects. Growth hormone levels will be drawn intermittently from the IV at specified times for a period of two hours. If the IV stops working during the test, it is important that it be restarted so the samples may be obtained at the specified times.

The purpose of the testing is to determine if you are GH deficient or not and if so, whether you are eligible for GH therapy. In order to start GH treatment, you will have one, sometimes two simulation tests to be performed. Your doctor will decide the number of tests and will interpret the test results for you. It may take several weeks for your doctor to receive and review the test results. You should discuss the results and the possibility of growth hormone treatment with your doctor.

Summary
Your doctor will prescribe GH replacement and other hormone replacement if you are deficient in GH and other pituitary hormones. Remember that each hormone has a specific function in your body. Replacement medication is very important, and so is your compliance with the medications. If you have any questions don't hesitate to call your doctor, nurse, or the MAGIC Foundation for resources.

Contributing Medical Specialist:

Kevin Yuen, MD, FRCP (UK), FACE
Professor of Medicine
Medical Director, Barrow Pituitary Center and Barrow Neuroendocrinology Clinic
Phoenix, Arizona

Resources

• Download a printable version of the Adult Growth Hormone Deficiency brochure

• Download a printable version of The Transition from Child with Growth Hormone Deficiency brochure

• Download a printable version of the Evaluation Process of Adults with Growth Hormone Deficiency

• "LIKE" The MAGIC Foundation's Facebook page

• Join our closed AGHD Facebook group. After you request to join, please message an admin to gain access or email Kelly at adultghd@magicfoundation.org

• Would you like to speak to someone about Adult Growth Hormone Deficiency? If so, call The MAGIC Foundation at 800-3MAGIC3 or (630) 836-8200 or email us