Introduction

Patients who have had pituitary surgery or radiation for the treatment of Cushing’s Disease, or whom have large pituitary adenomas, are at risk for adult growth hormone (GH) deficiency. Following pituitary surgery or radiation, if a patient is already lacking normal secretion of three or four pituitary hormones, then there is a 95% chance that the patient is GH deficient. In patients who have had pituitary surgery or radiation, there is a 25% chance that the patient will be GH deficient even if secretion of other pituitary hormones is normal. Thus, if pituitary surgery or radiation has been undertaken, such as to treat Cushing’s disease, GH deficiency should be evaluated.

What is Growth Hormone?

Growth hormone (GH) is a protein hormone that is produced by the pituitary gland. The pituitary gland releases GH periodically in “pulses” through the day, with most of the GH released during sleep at night. Once released into the bloodstream, GH attaches to most tissues, including bones and muscle. GH also binds to the liver and causes the liver to produce insulin-like growth factor-1 (IGF-1). IGF-1 has growth-like effects on many tissues as well. GH has an important role in allowing bones to grow and is critical for normal growth in children. In adults, GH helps maintain bone strength and prevents bone loss, which can lead to weak bones, called osteoporosis. GH also has effects on muscle (GH builds up muscle) and fat tissue (GH helps reduce fat). Therefore, GH is a very important hormone for maintaining body composition by allowing normal musculature to develop, while minimizing fat. Athletes take advantage of this by injecting high and unsafe doses of GH in order to gain even further muscle mass. In addition, GH has an active role in maintaining psychological and cognitive functions in normal adults. Therefore, GH is needed by both children and adults to allow for normal growth and maintenance of body composition, along with maximizing quality of life.

Growth Hormone Deficiency

GH deficiency is caused by low or absent production of GH by the pituitary gland. In children, GH deficiency results in poor growth leading to short stature. Since adults have already achieved their maximal height, loss of GH does not impact height, but does lead to loss of bone density. Lower bone density can lead to osteoporosis, where bone density is weakened causing an increased risk for fracture. Lower GH levels also lead to changes in body composition, with a loss in muscle mass and a gain in fat. The decrease in muscle translates into poor muscle function and decreased exercise capacity. In GH deficient patients, the fat accumulates largely in the mid, or abdominal, area. This type of fat is referred to as visceral fat, and this is associated with an increased risk of diabetes, elevated cholesterol levels, and premature disease of the blood vessels, called atherosclerosis.

Patients with GH deficiency tend to describe a worsening quality of life. People describe loss of energy, and overall loss of interests in their usual activities, jobs, or hobbies. Some people feel that they are more socially isolated, as they tend to stay home instead of meeting with others and socializing. Mild depression has been described with GH deficiency as well. The loss of energy with GH deficiency may be the main presenting complaint for patients. Often, people with GH deficiency describe that something is missing, and that they do not feel quite right. Sometimes, it is the partner who notices that the patient has lost interest, including sex, and it is the partner who raises this concern to the treating physician. GH deficiency has also been associated with reduced cognitive function, including difficulties with short term memory and ability to make simple calculations.

What causes GH deficiency?

Any disease or therapy that involves the pituitary gland can lead to GH deficiency. For example, whenever pituitary surgery or radiation is performed, there is a risk that normal secretion of pituitary hormones will be affected. Of all of the pituitary hormones, GH is the most commonly deficient after surgery or radiation. GH deficiency can be caused by tumors in or around the pituitary gland. Such tumors compress the normal gland preventing adequate GH release into the bloodstream. The most common type of tumor that causes GH deficiency is a pituitary tumor. Also, trauma to the head can cause GH deficiency. This is usually in the setting of severe brain injury, but repeated mild trauma to the head can cause GH deficiency as well.

Diagnosis of GH Deficiency

Once a diagnosis of adult GH deficiency is made, then GH replacement is initiated. The goal is to replace the GH levels to a normal, adult range and to reverse the consequences of GH deficiency. Because pituitary surgery is the mainstay of therapy for Cushing’s disease, GH deficiency may be detected following surgery and a diagnosis of GH deficiency should be considered. The assessment for GH should be put off for at least 3 months following pituitary surgery.

Diagnosis of Adult GH Deficiency

The diagnosis of GH deficiency is based upon blood testing of GH and IGF-1 levels. The pituitary gland releases GH in pulses throughout the day and night (mostly at night), but GH disappears rapidly from the bloodstream. Because of this, a random blood GH is usually low or undetectable during the day in both normal and GH deficient patients. Therefore, a GH blood level drawn randomly (anytime during the day) has no value for testing for GH deficiency. Instead, a blood IGF-1 measurement and GH stimulation tests are used to show the presence of GH deficiency. An IGF-1 value serves as a marker of how much GH has been circulating in the blood, and is a good screening indicator for GH deficiency. Patients with GH deficiency usually have low IGF-1 levels. Because IGF-1 levels decline with age, and are different between men and women, it is important to compare values that are matched for age and gender. In patients with GH deficiency, low IGF-1 levels alone can be diagnostic, but in most cases a stimulation test will be required. Some patients may have normal IGF-1 (usually low normal) and still be GH deficient.

Stimulation tests are used to confirm a diagnosis of GH deficiency. There are a number of different GH stimulation tests that utilize different drugs. The concept here is that, compared to a normal pituitary gland, a pituitary gland with low amounts of stored GH will release less GH into the bloodstream after a stimulation test. A normal response is defined as a certain cut-off blood GH level measured over a period of time after the drug is given. There are a number of different GH stimulation tests, including an insulin tolerance test (ITT) and a glucagon test. In the ITT, insulin is given subcutaneously to lower the blood sugar (glucose) level. As the glucose level falls, the body responds by making more GH to counter the low glucose value. In a normal person, the GH levels should rise above a specific cut-off value. Similarly, a glucagon test involves administration of this drug, followed by a rise and then fall of the glucose values. During the fall in blood glucose levels following the glucagon, the pituitary gland is stimulated to release more GH into the bloodstream. These tests take up to two or three hours, and GH levels are measured by blood tests during this time. The ITT needs to be monitored by a physician as very low blood glucose levels may occur. The testing is done in the outpatient setting and subjects may be instructed not to eat or exercise prior to the test.

Treatment of GH Deficiency

Following a diagnosis of GH deficiency, the physician will have a discussion with the patient regarding the benefits and risks of GH replacement therapy. GH is self-administered daily using a pen that includes a cartridge and a needle. A nurse usually meets with the patient prior to starting the GH for instructions on how to change the drug cartridge, how to administer the drug, and how to dispose of the needles. The starting dose of GH is usually low, with a steady increase in the dose at 4-8 week intervals based on clinical response, side effects and blood IGF-1 values. The dose is usually increased slowly to try to prevent side effects from a rapid increase in dosing. When following the IGF-1 levels, low IGF-1 values generally indicate a need for a higher dose, while high IGF-1 values indicate that the dose is too high. In most cases, the maintenance dose is determined based on patient tolerance of therapy, rather than absolute IGF-1 concentrations. Once the maintenance dose is reached, there is usually another 3-4 month period before the full benefits of GH therapy are realized.

There are certain caveats to dosing. Women who take oral estrogens require a higher dose of GH then do women not on estrogen or on transdermal estrogen, and for men. Women are instructed to tell their physician if they start or stop oral estrogens during treatment, as this will affect the response to the GH. Also, older patients usually require lower doses of GH than younger patients.

Side effects of GH may include salt and water retention, which can lead to swelling, high blood pressure, joint pains, shortness of breath, and headache. Carpal tunnel syndrome (numbness, tingling, or shooting pain in the thumb, index and middle finger) can occur as well. Patients are instructed to contact the treating physician if any of these symptoms occur, as temporary withdrawal of the GH can help resolve these issues. Once these symptoms have resolved, then the GH can usually be restarted at a lower dose.

Because glucose levels can rise with GH therapy, the physician will monitor blood sugar levels closely in a patient with diabetes mellitus. Initially, GH replacement can aggravate diabetes, but later improves control. Diabetes is not a contraindication to therapy.

Other tests that need to be monitored include thyroid and cortisol levels. GH therapy can lead to a reduction in blood tests for both of these, and the thyroid and glucocorticoid (steroid) replacement doses may need adjustment.

There are several contraindications to GH therapy that need to be considered. One such contraindication is an actively growing tumor. There is no evidence that GH increases the rate of tumor growth, but if a patient has a residual tumor, then tumor size by MRI scan should be followed. Also, it is recommended that patients who have had cancer be cancer free for 5 years prior to beginning therapy. There is no clear evidence that GH causes cancer, but there is a concern that GH can provoke cancers to grow. Another reason for not beginning therapy is proliferative retinopathy in a patient with diabetes.

To determine that the GH is effective, there is specific information that is collected prior to and while receiving therapy. Bone density tests are useful for demonstrating loss of bone density prior to starting GH, and should be performed in follow up to demonstrate improvement in bone density. Blood lipid profiles, blood sugar, weight, waist and hip circumference, blood pressure and answers to an easy to complete quality of life questionnaire can be measured to demonstrate benefit as well. These are useful for showing improvements to patients as well as insurance companies.

What should the Patient Expect?

Though individuals may feel better early after starting the GH, subjects are instructed to be patient with the GH as it may take up to 9-12 months before full benefits are experienced. Subjects are instructed to stay compliant with the GH shots, as they may note loss of energy if several doses are missed. Generally, patients notice an increase in energy, less fatigue, an increased ability to exercise, improved cognitive function and a return to their normal social life. Weight loss may not be experienced, but there is an overall shift towards greater lean muscle mass and loss of abdominal fat. Bone density usually takes at least 18 months to improve, and repeat bone density testing should not be performed for at least that duration .

Author: Dr. Laurence Katznelson, MD (Winter, 2009)

Editor’s Note: Dr. Laurence Katznelson is the Medical Director of the Pituitary Center at Stanford University School of Medicine