Growth hormone use and abuse
Growth hormone plays an essential role in human growth and development; deficiency results in short stature and other defects, whereas high levels can cause excessive growth and acromegaly. In addition to recognized medical indications for replacement, growth hormone has come to public attention because of its use by athletes to enhance performance (doping). This chapter covers the latest evidence about growth hormone physiology, therapeutic use, abuse, and detection.
Growth hormone (GH) is the most abundant hormone in the anterior pituitary gland; it is a single-chain peptide hormone produced and secreted by somatotroph cells in the anterior pituitary gland in two molecular forms; 22-kilodalton (kDa) GH is more abundant than the 20-kDa form, but their biologic activities are similar. Measuring individual GH isoforms plays a key role in detection of doping by athletes. Endogenous GH production is highest during puberty, decreasing by middle age to only about 15% of peak levels.
2. How does GH secretion occur?
GH is secreted in a pulsatile fashion, mostly at night. Factors that increase secretion include sleep, exercise, trauma, and sepsis. Obesity and increasing age reduce GH secretion.
3. How is the release of GH regulated?
GH secretion is stimulated by GH-releasing hormone (GH-RH) and inhibited by somatostatin, both from the hypothalamus. Ghrelin, a gastric peptide, also stimulates GH release. Another major regulator of GH production is insulin-like growth factor-1 (IGF-1), which acts at the pituitary to directly inhibit GH production and at the hypothalamus to inhibit the production of GH-RH and to stimulate somatostatin.
As its name implies, GH stimulates both linear growth and growth of internal organs (Table 26-1).
TABLE 26-1.
ACTIONS OF GROWTH HORMONE AT SPECIFIC SITES
| TARGET SYSTEM | ACTIONS |
| Liver and muscle | Increases nitrogen retention, amino acid uptake, and protein synthesis |
| Cardiovascular | Increases cardiac muscle mass and cardiac output at rest and during maximal exercise |
| Hematologic | Increases plasma volume and red cell mass |
| Skeletal tissue | Increases bone mineral density and bone turnover |
| Connective tissue | Increases collagen turnover at nonskeletal sites, including tendons |
| Metabolism | Increases rates of sweating and thermal dispersion during exercise |
| Endocrine: | |
| Acute | Increases the uptake and utilization of glucose by muscle; antagonizes the lipolytic effect of catecholamines on adipose tissue |
| Chronic | Reduces glucose utilization, enhances lipolysis, and increases lean body mass |
5. Does GH exert all of its effects directly?
No. Many of the effects are mediated by IGF-1, which is also called somatomedin C. GH stimulates the production of IGF-1 in peripheral tissues, particularly the liver. In patients with GH resistance, which is often due to GH receptor mutations, some effects of GH can be achieved by IGF-1 administration; IGF-1 has been approved for treatment of GH-resistant patients.
6. What causes excessive GH secretion, and what are the consequences?
The major cause of excessive GH secretion is a GH-producing pituitary tumor. GH excess during childhood results in gigantism. Numerous historical examples have been noted, including Robert Wadlow, the “Alton giant,” who reached a height of just over 8 feet 11 inches and wore size 37AA shoes. GH excess after epiphyseal closure results in acromegaly.
7. What conditions are associated with GH deficiency?
GH deficiency can be congenital (genetic mutations) or may result from damage to the pituitary gland by intracranial tumors, surgery, radiation therapy, trauma, and a variety of infiltrative and infectious diseases. Adult-onset GH deficiency is much less common than onset during infancy and childhood and is often related to a preceding event such as radiation exposure or trauma.
8. What are some common signs and symptoms of GH deficiency?
GH deficiency in childhood results in short stature; similar effects are seen in GH resistance. GH deficiency in adults causes greater adiposity and decreases in lean body mass, bone density, extracellular water, cardiac function, muscle force and strength, and exercise performance. Patients have reduced exercise capacity and strength levels and often complain of lethargy and fatigue. Quality of life may be diminished, with manifestations of depression, anxiety, mental fatigue, and decreased self-esteem. Excessive intraabdominal fat is associated with an increased risk of cardiovascular disease, which is the predominant cause of death in GH-deficient patients.
9. Where do we get the GH used therapeutically?
Historically, GH was derived from human cadavers; however, modern techniques have allowed for abundant production of biosynthetic GH, which is identical to the endogenous form.
10. Besides availability, what problem was associated with GH derived from human cadavers?
Creutzfeldt-Jakob disease, an uncommon, rapidly progressive, and fatal spongiform encephalopathy, has been reported to result from iatrogenic transmission through human cadaver pituitary tissue. More than 30 young adults who received human cadaver pituitary products have died of this disease, and at least 60 to 70 cases of Creutzfeldt-Jakob disease have been identified in recipients.
11. List the uses of GH approved by the U.S. Food and Drug Administration (FDA).
Historically, the only approved indication for GH therapy was treatment of short stature in children with GH deficiency. Currently, GH is also approved for treatment of short stature that is idiopathic or is associated with Turner syndrome, Prader-Willi syndrome, Noonan syndrome, or progressive chronic renal insufficiency in children. GH is also approved for treatment of wasting in patients with acquired immunodeficiency syndrome (AIDS) and for replacement in GH-deficient adults.
12. List the potential uses of GH.
GH has potential uses in the following conditions: (1) Russell-Silver syndrome, (2) chondrodysplasia in children, (3) steroid-induced growth suppression, (4) short stature associated with myelomeningocele, (5) any severe wasting state (e.g., wounds, burns, cancer), (6) normal aging, (7) non–islet cell tumor hypoglycemia, (8) gonadal dysgenesis, (9) Down syndrome, (10) short stature associated with neurofibromatosis, (11) human immunodeficiency virus (HIV)–associated adipose redistribution syndrome, and (12) osteoporosis.
13. How does GH help GH-deficient adults?
The reported beneficial effects in GH-deficient adults are an increase in muscle mass and function, reduction of total body fat mass, and increased plasma volume as well as improved peripheral blood flow. Reductions in serum total and low-density lipoprotein (LDL) cholesterol, reduction in diastolic blood pressure, a trend toward reduction in systolic blood pressure, and beneficial effects on bone metabolism and skeletal mass have also been documented. In addition, an improvement in psychological well-being and quality of life can occur with GH replacement.
GH is administered by subcutaneous injection. In children, the dose can be divided into twice-weekly, thrice-weekly, or daily regimens. Daily injections appear to give greater growth velocity than less frequent administration. In adults with GH deficiency, replacement is usually given daily.
15. Why is GH used as an ergogenic aid by athletes?
Some athletes have used GH in an effort to improve performance. Supraphysiologic doses of GH have been reported to increase lean body mass and reduce body fat in trained athletes. However, most studies suggest that GH administration has no beneficial effects on muscle strength, growth, or exercise performance in non–GH-deficient adults except for very modest gains in anaerobic exercise capacity. In general, GH appears to have less significant impact on performance than androgenic steroids. The possibility for modest gains with low likelihood of being caught may be the reason some athletes have used GH in the past.
16. What developments have been made in testing for GH abuse?
Prior to 2004, there was no reliable method to detect exogenous GH administration because of difficulties distinguishing it from endogenous hormone. After years of study and international collaboration, scientists developed a test that has been endorsed by the World Anti-Doping Association (WADA). In February 2010, the test identified the first GH doper, a British rugby player who was banned from competition for 2 years for the infraction. The test was used experimentally in 2004, and became widely available by 2010. The test’s limitations include requiring a blood sample and the inability to detect GH use more than 1 or 2 days prior to testing.
17. Why was GH abuse so difficult to detect in the past?
GH was difficult to detect in the past because exogenously administered GH is identical in structure to endogenous hormone, so simply detecting GH in a blood sample was not evidence of doping. Additionally, endogenous GH is secreted in a pulsatile manner; therefore, detection of an increased level on random testing could simply reflect a natural peak, because GH secretion is stimulated by acute exercise. Cadaveric GH has also been used for doping purposes and is difficult to detect because of normal ratios of GH isomers.
18. How can GH abuse in athletes be detected?
GH doping can be detected by two distinct methods. The first method measures the ratio of the two isoforms of GH, and the second method measures the markers of GH action such as IGF-1 and procollagen III N-terminal propeptide (P-III-NP).
19. How prevalent is GH use among athletes?
The prevalence is not known, but GH use is thought to be widespread. Use of GH is probably not as extensive as use of anabolic-androgenic steroids. One limiting factor is the expense. Even a 1-month supply may cost several thousand dollars, depending on dosages.
20. What are the adverse effects of the therapeutic use of GH in adults?
Fluid retention causing edema and carpal tunnel syndrome are common in adults but not in children. Arthralgias, myalgias, paresthesias, and worsening glucose tolerance are also common and may be present in up to one third of patients taking GH. Other potential side effects include gynecomastia, pancreatitis, behavioral changes, worsening of neurofibromatosis, scoliosis and kyphosis, and hypertrophy of tonsils and adenoids.
21. What are the adverse effects of GH in children?
Intracranial hypertension has been reported in children; this is most common in children with renal disease, although it has also been observed in children with GH deficiency and in girls with Turner syndrome. GH therapy is associated with an increased risk of slipped capital femoral epiphysis in the same three groups of children. Children with GH deficiency due to deletion of the GH gene may develop antibodies to GH, with secondary growth deceleration; this phenomenon is rare in other children.
22. What adverse effects occur in athletes using GH?
Little is known about side effects of GH use in athletes. Chronic abuse of supraphysiologic GH doses may lead to features of acromegaly, osteoarthritis, irreversible bone and joint deformities, increased vascular, respiratory, and cardiac abnormalities, hypertrophy of other organs, hypogonadism, diabetes mellitus, abnormal lipid metabolism, increased risk of breast and colon cancer, and muscle weakness due to myopathy. Use of GH in combination with anabolic androgenic steroids may increase left ventricular mass and cause cardiac remodeling.
23. Can GH reverse the natural aging process?
No. However, alternative medicine companies promote products alleged to stimulate increased production of GH in hopes of reversing normal aging. This theory has been sustained partly by a study suggesting that diminished secretion of GH is responsible for the effects of aging, including increased adipose tissue, decreased lean body mass, and thinning of the skin. Although GH replacement has a role in deficient individuals, no studies have shown that supplemental GH can reverse physiologic aging.
KEY POINTS 1: GROWTH HORMONE USE AND ABUSE
1. Growth hormone secretion is stimulated by exercise, stress, trauma, and signaling by growth hormone–releasing hormone and grehlin. Inhibition occurs by feedback from somatostatin and IGF-1.
2. Growth hormone abuse to enhance performance is thought to be prevalent in athletes, but little evidence supports meaningful performance enhancement, except for some increase in anaerobic exercise capacity.
3. Detection of GH doping has become possible on a large scale, including at the Olympic Games. Current testing relies on either altered GH isoform ratios or altered markers of GH action.
4. Long-term effects of supratherapeutic doses of GH in athletes are not known, but there is concern about multiple possible negative effects.
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