Adult Growth Hormone Deficiency Syndrome
The following article is composed of excerpts from a manuscript published by D.M. Cook, W.H. Ludlam, and M.B. Cook in Advances in Internal Medicine, Volume 45, pages 297-315 (2000).
The adult growth hormone (GH) deficiency syndrome has been defined recently and separated from the childhood deficiency syndrome. With the availability of potentially unlimited supplies of recombinant engineered human GH for clinical use,
endocrinologists must learn how to diagnose and treat this syndrome. However, diagnosis remains controversial and arbitrary, dosing guidelines have yet to be defined, and realistic expectations for patients receiving GH must be further delineated. The potential for abuse of this hormone must be kept in mind, both for improper indications such as performance-enhancing aids for athletes and for clinically unproven indications such as obesity and prevention or delaying of the aging process.
Symptoms of the adult GH deficiency syndrome are non-specific and in general cannot be separated from other debilitating illnesses such as depression, hypogonadism, or hypothyroidism. Two symptoms have stood out in several studies: a decrease in energy and feeling of social isolation. The former symptom can best be ascertained by asking the patients what hobbies or pastime activities they have enjoyed and if they are continuing to do so. Feelings of social isolation can be exposed by asking patients if they get out and meet their friends as much as they used to. Two important points should be made concerning symptoms. The first is that patients may not realize they have symptoms until they are treated and experience unexpected improvements. The second is that a spouse or partner can often be more objective about the patient’s changing behavior and thus can offer a better assessment of those changes. This is true for deficiency symptoms as well as for their resolution after successful therapy.
Just as the primary focus of childhood GH deficiency remains linear growth; in adults the primary focus is symptoms. To successfully interact with patients during GH therapy, the endocrinologist must anticipate four sets of symptoms, which include: symptoms of the syndrome itself, “start-up” symptoms related to the impact of initiating therapy, symptoms related to too much GH, and lastly, symptoms of improvement. Symptoms occurring at therapy initiation include muscle or joint pain, headaches, and blurred vision. Presumably these symptoms are created by the sudden retention of sodium and water. These important symptoms should be anticipated in susceptible individuals, such as the elderly and those more severely deficient.
Symptoms of excess GH include musculoskeletal pain, peripheral edema, and carpal tunnel syndrome. The patient’s tolerance of therapy often will determine the final dose of GH, even though serum IGF-1 concentrations do not suggest the dose is excessive. Increasing the dose slowly, that is, every 6 to 8 weeks, helps to minimize side effects. Patients often report carpal tunnel symptoms after each dose increment. These symptoms disappear after 3 or 4 days of therapy. Others will have persistent carpal tunnel signs and symptoms and will wish to have this problem surgically repaired rather than discontinuing therapy and relapsing to deficient syndrome status.
Improvement symptoms include return of energy and an increase in alertness. Many times, spouses or children of the patient will notice these improvements first. Return of energy is the symptom most often reported and is the main reason patients want to continue therapy. Many times this is confirmed by interruption of the drug, either voluntarily or involuntarily (i.e., forgetting the medicine for a few days). The patient quickly realized that he or she is not functioning as well without the drug. Thereafter, patients will seldom interrupt therapy.
Sampling random serum GH is of no value, because normal individuals have random GH levels that are low throughout most of the day. A stimulation test is necessary to confirm the diagnosis. The Food and Drug Administration
(FDA) has established criteria for a normal response after a standard provocative stimulus. It is > 5 ng/mL when using a nonspecific radioimmunoas say that measures most of the circulatory molecular species of GH and > 2.5 ng/mL when using the more specific immunoradiometric assay (IRMA), one that quantitates the major biologically active molecular species of GH, which is the 22,000 molecular weight (22K) molecule.
Signs of GH Deficiency
The physical signs of GH deficiency consist of body composition changes, including an increase in fat and a decrease in lean body mass. The fat deposition is predominantly in visceral fat but also occurs in subcutaneous fat. Lean body mass changes include a decrease in both muscle and bone mass. The latter has been associated with an increase in fracture rates. Deficiency of GH also leads to increased total cholesterol and triglycerides, and a decrease in high-density lipoprotein (HDL) cholesterol. This profile of an increase in visceral fat and other cardiovascular risk features has presumably led to an increase in cardiovascular mortality.
It has become increasingly clear that doses once thought to be reasonable for adults were excessive and associated with side effects and elevated IGF-1 concentrations. Original studies by Ho and others have suggested that normal postmenopausal women secrete more GH when given oral vs. transdermal estrogen. Using IGF-1 concentrations and symptoms tolerance, we have translated these original observations to GH replacement therapy. We have found that it takes more GH to bring IGF-1 into the normal range when a woman is taking oral, rather than transdermal, estrogen. The dosage for men is similar as for women receiving transdermal estrogen, but men require less than women who are taking also oral estrogen.
Patients should be monitored with IGF-1 concentrations every 6 to 8 weeks until the IGF-1 is in the mid to high normal range for age and sex. Symptom tolerance also may dictate final dose. Patients with musculoskeletal pain and carpal tunnel symptoms or aggravation of hypertension may wish to cut back on their dose. Many times these symptoms are associated with initiation of therapy or a change to a higher dose. If symptoms appear within the first 10 days of either of these clinical situations, we suggest patients continue taking their dose because these symptoms will usually disappear. Symptoms that persist beyond 2 weeks probably will not resolve and should be corrected by reducing to the previously acceptable dose. Some patients will “settle” for an IGF-1 that is not in the normal range, yet feel so much better while taking a sub therapeutic dose that they retain it as their final dose. Patients should be cautioned that it usually requires two to three dose changes before a final plateau dose is reached. Also, patients should be advised that complete resolution of the syndrome may take 8 to 12 months.
Interaction with other hormones
Panhypopituitary patients are frequently taking other hormones in addition to GH. These usually include testosterone or estrogen, thyroxin, and cortisol. Of these hormones, none except cortisol appear to be affected by GH therapy. Although clinically there have not been reports of adrenal insufficiency with GH therapy, there is a theoretical concern. One report suggests that cortisol metabolites in urine increase during GH therapy. There is an increase in cortisone metabolites. This line of evidence suggests an increase in the enzyme 11-hydroxysteroid dehydrogenase, which is biologically inactive. Another hormonal impact is on glucose control. Patients, especially those with type 2 diabetes, frequently have aggravation of their diabetic control during the first 6 months of therapy. Eventually their diabetic control improves as they lose fat and accumulate muscle and lose weight.
The diagnosis of the adult GH deficiency syndrome from a clinical and laboratory standpoint has been reviewed. Therapy guidelines and monitoring should focus on the patient’s symptoms and IGF-1 concentrations from a laboratory standpoint. Successful patient/physician interaction depends on physician awareness of the symptoms of the deficiency syndrome and symptoms associated with therapy. Successful therapy with
GH almost always results in an extremely satisfied patient, family, and physician.
The full text and references can be found in: Advances in Internal Medicine, Volume 45, pages 297-315. These excerpts are printed with permission of Mosby, Inc.