testosterone, steroids, dianabol, hgh

Human Growth Hormone: What Can It Do For Your Growth, Human? Mark H. Davino, M.D. April 28, 2008 INTRODUCTION Growth hormone (GH), a product of the anterior pituitary gland in humans, has a complex role in basic metabolism, promoting muscle and bone mass as well as decreasing fat mass. Recombinant GH was developed in 1983 and currently has only several Food and Drug Administration (FDA)-approved indications in adults, which include GH deficiency, HIV wasting, and short-bowel syndrome. Additional clinical indications exist in children, which include Turner Syndrome, Noonan Syndrome, intrauterine growth retardation and more recently Idiopathic Short Stature (2003). The benefits of GH therapy have been well studied in the above clinical scenarios, but research has not proven that benefits can be extrapolated to other patient populations. Since GH levels have been shown to decline steadily in life, GH supplementation has been purported to be a potential “fountain of youth” or “syringe of youth” in the aged population. Research, however, indicates that beneficial effects of GH supplementation in this population are negligible and the risks are disproportionately high. Still, since GH does increase lean body mass and decrease fat mass, and, in some instances, improve exercise capacity, it has led to ill-informed consumer demand for GH, and, where there is demand, there is money to be made. Annual worldwide sales of GH, fueled in part by “off-label prescriptions,” are estimated to be $1.5 to $2 billion [1], and it has been suggested that 30% of GH prescriptions in the United States are for indications not approved by the FDA, which would include anti-aging and athletic performance [2]. The injectible form of HGH costs close to $1000 per month. A significant number of on-line and other illegal resources, i.e., drugs by mail, have cropped up leading to the misuse of GH supplementation, both in relatively healthy persons and in athletes. Even less research exists for studying GH supplementation in athletes, and athletes have risked their livelihoods, legacies, and personal health without proof of benefit. Since athletes, either intentionally or unintentionally, serve as role models for the youth and young adults of this country, primary care physicians should be educated and be in a position to dissuade their patients from illegally obtaining and using human growth hormone. BACKGROUND Growth hormone (GH) is the most abundantly produced hormone of the anterior pituitary gland and is produced by the pituitary somatotroph cells. GH is a 22 kDa protein that is a product of the GH gene family which is comprised of five distinct genes, all located on chromosome 17q22 (Figure 1) [3]. GH secretion is regulated by hypothalamic and peripheral factors acting on the somatotroph cells (Figure 2). Growth hormone-releasing hormone (GHRH) stimulates GH secretion from the pituitary, and somatostatin inhibits GH secretion, each while binding to specific cell-surface receptors. In addition, hypoglycemia and ghrelin (a gastrointestinal peptide) stimulate GH production and IGF-I (via negative feedback) as well as hyperglycemia inhibit its production. GH secretion is pulsatile, with higher peaks at night than during the day, and with immeasurable serum values in between pulses. There are approximately 10 pulses of GH secretion per day, each lasting approximately 90 minutes, with each pulse separated by less than 90 minutes [4]. It is believed that somatostain maintains tonic inhibition of somatotrophic cells, while GHRH enables breakthrough activation of the same cells. Detecting levels of growth hormone in serum is unreliable, although, provocative testing with either insulin-induced hypoglycemia or arginine remains the gold standard with the former test being more sensitive but more dangerous [5]. Fortunately, GH levels directly correlate with serum levels of IGF-1 and its major binding protein, IGFBP-3. These values are routinely used in screening for GH deficiency and in clinical studies testing GH therapy. GH exerts a number of physiologic effects throughout the body (Figure 3), which include: 1) stimulation of protein synthesis 2) increased lipolysis and lipid oxidation, which subsequently leads to the mobilization of stored triglyceride 3) antagonism of insulin action and 4) sodium and water retention. In children, GH serves to stimulate bone growth directly and also indirectly via actions of IGF-I. In fact, the majority of GH effects occurs via stimulating the production of insulin-like growth factor I (IGF-I) [6]. Although IGF-I secreting cells are located throughout the body, and can function in both endocrine and paracrine or autocrine fashions, GH stimulates IGF-I production specifically from hepatic cells. Once manufactured, IGF-I binds with IGF-binding proteins and ALS (acid-labile subunit) to form a stable ternary complex with a plasma half-life of 16 hours. Greater than 99 percent of IGF-I in circulation exists in the bound state, allowing delivery to peripheral tissues. Target cell types that have IGF-I receptors and respond to IGF-I include chondrocytes, osteoblasts, keratinocytes, skeletal myoblasts, astrocytes, glial cells and end-terminally differentiated neurons [7]. GH production begins early in fetal life and continues throughout life, though at progressively declining rates. In fact, daily GH rates of secretion decline from a peak of approximately 150 μg/kg during puberty to about 25 μg/kg by age 55 years, a decline that parallels the age-related decline in body mass index (Figure 4) [8]. GROWTH-HORMONE DEFICIENCY Growth-hormone deficiency in adults results from numerous etiologies which result in panhypopituitatarism and include pituitary tumors (or from its excision and subsequent irradiation; 76%), an extrapituitary tumor (13%), idiopathic (8%), sarcoidosis (1%) or Sheehan’s syndrome (0.5%) [9]. Patients with panhypopituitarism routinely are given replacement therapy with steroids, thyroid hormone and sex hormones but are less often given growth hormone therapy perhaps because it is cost prohibitive. Nonetheless, multiple clinical trials conducted since the advent of recombinant human growth hormone have shown multiple physiological benefits, and GH supplementation is more strongly advocated for by The Endocrine Society Clinical Practice Guidelines [10]. GH replacement increases muscle mass and decreases subcutaneous and visceral fat mass [11, 12], and increases bone mineral density in men [12, 13]. The long-term effects of GH replacement have been shown in a small number of prospective studies, one of which followed 38 patients (mean age 28 +/- 4 years) with growth hormone deficiency (GHD) [14]. Twelve patients had idiopathic, isolated GHD while the remaining had complete pituitary failure. All 38 patients had IGF-1 levels at least 2 standard deviations below the accepted mean value for age and were followed for 3 to 5 years. Outcomes measured included anthropometry (height, weight, skinfold thickness), computed tomographic scanning of the abdomen and upper leg, bone densitometry, echocardiography, and bicycle ergometry. The initial GH dose of 9-27 μg/kg was gradually tapered to 11 μg/kg, with the goal of attaining physiologic IGF-1 levels. During the study, subcutaneous and intraabdominal fat decreased by 30.9% (P < 0.001) and 46% (P < 0.001), respectively, after 1 year, but demonstrated a partial regain thereafter (Figure 5). Muscle mass of the leg increased progressively by 28.7% (P < 0.001) (Figure 5). Bone mineral density at the lumbar spine, femoral neck, and trochanter gradually increased by 9.6%, 11.1%, and 16.2%, respectively (all P < 0.001) (Figure 6). Left ventricular mass surpassed baseline values after 1 year by 14.1% (P < 0.001) but returned to baseline values thereafter. Stroke volume increased by 16.3% (P = 0.002) and cardiac output increased by 33.4% (P < 0.001) (Figure 7). Maximal work load increased from 189 +/- 30 to 232 +/- 41 watts (P < 0.001) (Figure 8). Overall, GH replacement showed definitive physiologic and anatomical benefits and was generally well-tolerated. The majority of side-effects occurred during the first few months of treatment and included muscle or joint stiffness, peripheral edema, paresthesias, gynecomastia and thirst. Two patients became hypertensive and were started on anti-hypertensive medications. GROWTH HORMONE IN THE ELDERLY The world’s population continues to age each year and at unprecedented rates, with an increasingly larger portion of the population being 60 years of age and older. According to the World Assembly on Aging (Population Division; United Nations), the proportion of older persons was 8% in 1950 and 11% in 2007, and is projected to reach 21% in 2050 [15]. In addition, by 2050, it is predicted that the number of older persons in the world will exceed the number of young for the first time in history. This transformation of population demographics is taking place more rapidly in developed countries such as the United States, where almost one fifth of the populations was aged 60 or older in the year 2000. By 2050, this proportion is expected to reach one third. Growth hormone (GH) levels, and thus IGF-1 levels, decline steadily in life after peaks in the neonatal period and in adolescence. In fact, less than 5% of healthy men 20 to 40 years old have plasma IGF-1 levels of less than 350 U per liter, but the levels lower than 350 U per liter in 30% of healthy men over the age of sixty [16]. One of the first randomized controlled trials involving human growth hormone (HGH) sought to elucidate the effects of growth hormone supplementation in the aged population [17]. In this study, 21 healthy men aged 61 to 81 years old, who had plasma IGF-1 concentrations of less than 350 U per liter, were recruited from the community via newspaper advertisements. The subjects were randomly assigned, in a 3:2 ratio, to two study groups, with group 1 receiving 0.03 mg/kg recombinant HGH three times weekly and group 2 being followed clinically. Neither group received intervention during a 6 month baseline period. Group 1, however, received HGH during the 6 month treatment period that followed. At the end of each period, lean body mass, the mass of adipose tissue, skin thickness (epidermis plus dermis), and bone density at 9 skeletal sites were measured and compared (Figure 9). In group 1, the mean plasma IFG-1 level rose in the “youthful” range of 500 to 1500 U per liter during treatment, whereas in group 2 it remained below 350 U per liter. Six months of HGH supplementation in group 1 resulted in an 8.8% increase in lean body mass, a 14.4% decrease in adipose-tissue mass, and a 1.6% increase in average lumbar vertebral bone density (P < 0.05 in each instance). In group 2, there were no changes in lean body mass, adipose-tissue density or bone density (Figure 10). Only 2 statistically significant side effects were observed. In group 1 subjects, both the mean systolic blood pressure and fasting plasma glucose concentrations were higher (P < 0.05). No accumulation of extracellular water, edema, paresthesias, or injection site pain was observed. The findings of Rudman et al were published in the New England Journal of Medicine and helped foster the notion that HGH could serve as a “fountain of youth” for our rapidly expanding aged population. Rudman and colleagues’ studies are oft cited by self-help books and websites designed to perpetuate this belief. His study however was notably not blinded, only studied men, and lacked power (n=21) as well as length as only 6 months of actual treatment were administered. Also, an intention to treat analysis was not explored, and the IGF-1 levels of the subjects involved were lower than the vast majority of other aged persons. A more comprehensive, randomized, double-blinded, placebo-controlled parallel group trial was performed and reported by Blackman et al in the Journal of the American Medical Association (JAMA) in 2002 [18]. This study further examined the efficacy and safety of GH supplementation, as well as coincident sex steroid replacement, in healthy, U.S. community-dwelling men and women. Participants were randomized into one of four groups: 1) placebo alone (sex steroid and HGH) 2) sex steroid and HGH placebo 3) HGH and sex steroid placebo and 4) HGH and sex steroid. Sex steroid replacement for women included transdermal estradiol, 100 μg/d, plus oral medroxyprogesterone acetate, 10 mg/d, during the last 10 days of each 28-day cycle. Men received testosterone enanthate in biweekly intramuscular injections of 100 mg. The main outcomes measured after a 26 week examination period were lean body mass, fat mass, muscle strength, maximum oxygen uptake (VO2max) during treadmill testing, and adverse effects. The investigators found that HGH with or without sex steroids in healthy, aged women and men increased lean body mass and decreased fat mass (Figure 11). Sex steroid plus HGH increased muscle strength marginally (Figure 12) and VO2max in men (Figure 13), but women had no significant change in strength or cardiovascular endurance. In contrast to Rudman et al [17], adverse effects were discovered (Figure 14). Statistically significant adverse effects included edema in women (both GH and GH + sex steroid groups; P = 0.02 for both), carpal tunnel syndrome in men (GH + sex steroid group; P = 0.02) and arthralgias in men (GH group; P < 0.01). More importantly, diabetes developed in 5 men receiving GH and 1 man not taking GH (P = 0.06), and diabetes or fasting glucose intolerance occurred in 18 GH-treated men versus 7 not receiving GH (P = 0.006). In 2007, a metanalysis review of randomized controlled trials looking at the effects of GH in the elderly was published in the Annals of Internal Medicine which largely corroborated the findings of Blackman et al [19]. After reviewing 31 journal articles describing 18 unique study populations (220 total participants), the authors established participants treated with GH compared with those who were not treated with GH, decreased overall fat mass by 2.1 kg and increased lean body mass by 2.1 kg (both P < 0.001). These “small” benefits in body composition were counterbalanced by significant adverse effects including soft tissue edema (50%; range 23-89%), arthralgias (21%; range 0-50%), and carpal tunnel syndrome (19%; range 0-50%). Also, study subjects receiving GH were more likely to develop impaired fasting glucose, glucose intolerance or frank diabetes (22%; range 6-53%). HGH distribution and use as an anti-aging therapy remains illegal in the United States and has not been approved by the U.S. Food and Drug Administration. GROWTH HORMONE AND ATHLETIC PERFORMANCE Growth Hormone (GH) supplementation has proven benefit in body composition in patients with depressed GH levels, but has marginal effects on muscle strength and exercise capacity. There is, however, a striking lack of research trials examining the potential benefits of GH supplementation in persons with normal GH levels. Acromegaly results from persistent hypersecretion of GH and is usually the result of a GH-secreting pituitary adenoma. In acromegalics with long-standing supraphysiologic GH levels, the muscle volume is increased, but muscle strength and performance are not improved [20]. In addition, acromegalics typically suffer from conditions equivocal to those demonstrated in the aforementioned studies which include arthralgias, arthritis, carpal tunnel syndrome, hypertension, impaired glucose tolerance and diabetes mellitus. There was only one randomized, double-blind, placebo-controlled study of exogenous HGH on muscle power in trained athletes prior to 2002 [21, 22]. This study involved 22 adult male power athletes (age 23.4 +/- 0.5 years) from a sports club training 8-14 hours weekly for at least 6 months who were given HGH or placebo nightly for 6 weeks. The athletes followed there pre-established training regimen throughout the study. Three of the 11 subjects receiving HGH withdrew from the study because of edema of the fingers or carpal tunnel syndrome. Two subjects experienced these side effects and continued in the study with spontaneous resolution of the symptoms. The dose of HGH administered was similar to supraphysiologic dose used to treat children with Turner Syndrome, and is believed to be 2 to 3 times less than that used by athletes [22]. The authors of the study monitored urine to ensure no concomitant anabolic steroid use and special care was taken to ensure blinding and adherence. The results showed a significant increase in strength of the biceps and quadriceps in both the HGH test group AND the placebo group suggesting the increase in strength resulted from training alone and was not augmented by HGH. Lean body mass and weight were not affected by HGH administration. Subsequently, in 2005, researchers in Sweden published a randomized, double-blinded, placebo-controlled trial with the objective of studying the effects of HGH in healthy young men and women [23]. Thirty healthy and active young individuals who were not professional athletes were recruited from the local community. None of the participants were receiving medical treatment of any kind, nor suffered from any chronic medical conditions, and all women tested negative for pregnancy. After a baseline evaluation including complete history and physical, participants were randomized, with an even gender distribution, to placebo (n=10), low-dose (0.033 mg/kg/d) GH (n=10) or high-dose (0.067 mg/kg/d) GH groups (n=10). Subjects were treated for 28 days after which time power output and oxygen uptake on bicycle exercise, amongst other outcomes, were measured. The authors found, despite a significant elevation in serum IGF-1 (P < 0.0001), no effect of the low or high dosages of GH on maximum oxygen uptake during exercise (mean +/- SD for placebo, 45.2 +/- 1.6 to 45.2 +/- 2.1 ml/kg/min; GH low dose, 42.8 +/- 1.6 to 42.8 +/- 1.6 ml/kg/min; GH high dose, 44.8 +/- 3.4 to 44.8 +/- 2.2 ml/kg/min) (Figure 15). Also, there was no effect on maximum achieved power output during exercise (Figure 16). However, the authors did find a significant increase in weight for both low-dose GH (72.5 +/- 13.7 to 74.0 +/- 14.8 kg) and high-dose GH (67.2 +/- 10.5 to 69.0 +/- 10.9 kg) (P = 0.0279), but this was ascribed to fluid retention (increased extracellular water volume) rather than an increase in muscle mass. The study adequately examines the short-term effects of HGH supplementation in both young men and women, but does not explore the long-term benefits or risks of HGH, and it is a small study sample. CONCLUSIONS Recombinant human growth hormone (HGH) is an expensive medication that has several beneficial uses. It has been proven to increase lean body mass and bone strength while decreasing fat mass in patients with GH deficiency and in other select populations. However, these benefits cannot be extrapolated to other, relatively healthy populations. Since HGH supplementation in the elderly has a paucity of physiologic benefits, but well documented side effects, it should not be recommended, despite what some manufactures of health supplements declare. Furthermore, even though there is a dearth of clinical trials to elucidate the effects of HGH supplementation in athletes, preliminary research shows that there are no physiologic benefits, only risks. Primary care practitioners should take care to counsel against HGH abuse in their adolescent and young adult patients as well as in their elderly patients. RERERENCES 1. Bibby K, Davis J, Jones C. Biopharmaceuticals- moving to centre stage. BioPeople North American Biotechnology Industry and Suppliers’ Guide, IMS Global Consulting Web site. 2. Vance, M. Retrospective: can growth hormone prevent aging? N Engl J Med. 2003; 348:779-780. 3. Herrington, J, Carter-Su, C. Signaling pathways activated by the growth hormone receptor. Trends Endocrinol Metab 2001: 12:252. 4. Toogood, AA, Nass, RM, Pezzol, SS, et al. Preservation of growth hormone pulsatility despite pituitary pathology, surgery, and irradiation. J Clin endocrinol Metab 1997; 82:2215. 5. Raiti, S, Davis, WT, Blizzard, RM. A comparison of the effects of insulin hypoglycaemia and arginine infusion on release of human growth hormone. Lancet 1967; 2:1182. 6. Frank, SJ. Growth hormone signallling and its regulation: preventing too much of a good thing. Growth Horm IGF Res. 2001; 11:201. 7. Clemmons, DR. Physiology of insulin-like growth factor I. December, 2004. www.uptodate.com. 8. Giustina A, Veldhuis, JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 1998; 19:717. 9. Bates, AS, Hoff, W, Vant, Jones, PJ, et al. The effect of hypotituitarism on life expectancy. J Clin Endocrinol Metab 1996; 81:1169. 10. Molitch, ME, Clemmons, DR, Malozowski, S, et al. Evaluation and treatment of adult growth hormone deficiency: and Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2006; 91:1621. 11. Bengtsson, BA, Eden, S, Lonn, L, et al. Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 1993; 76: 309 12. Biller, BM, Sesmilo, G, Baum, HB, et al. Withdrawal of long-term physiological growth hormone (GH) administration: differential effects on bone density and bone density and body composition in men with adult-onset GH deficiency. J Clin Endocrinol Metab 2000; 85:970. 13. Baum, HB, Biller, BMK, Finkelstein, JS, et al. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency: a randomized, placebo-controlled trial. Ann Intern Med 1996; 125:883. 14. Ter Maaten, JC, De Boer, H, Kamp, O, Stuurman, L, et al. Long-Term Effects of Growth Hormone (GH) Replacement in Men with Childhood-Onset GH Deficiency. J Clin Endocrinol Metab 1999. 84:2373-2380. 15. World Population Ageing 1950 – 2050. Executive Summary; United Nations Department of Economic and Social Affairs, Population Division. 2007; 1-11. 16. Rudman D, Kutner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP. Impaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest 1981; 67:1361-9. 17. Rudman D, Feller AG, Mattson, DE, et al. Effects of Human Growth Hormone in Men Over 60 Years Old. N Engl J Med 1990; 323:1-6. 18. Blackman MR, Sorkin, JD, Munzer T, Harman MS, et al. Growth Hormone and Sex Steroid Administration in Healthy Aged Women and Men. JAMA 2002; 288:2282-92. 19. Liu H, Bravata DM, Olkin I, Nayak S, Hoffman AR, et al. Systematic Review: The Satefy and Efficacy Of Growth Hormone in the Healthy Elderly. Ann Intern Med 2007;146:104-115. 20. Frisch H. Growth Hormone and Body Composition in Athletes. J Endocrinol Invest. 1999;22 (5 Suppl):106-9. 21. Deyssig R, Frisch H, Blum WF, et al. Effect of growth hormone treatment on hormonal parameters, body composition and strength in athletes. Acta Endocrinologica 1993; 128:313-18. 22. Dean H. Does Exogenous Growth Hormone Improve Athletic Performance? Clin J Sport Med 2002; 12:250-53. 23. Berggren A, Ehrnborg TR, Rosen T, Bengtsson BA, et al. Short-Term Administration of Supraphysiological Recombinant Human Growth Hormone (GH) Does Not Increase Maximum Endurance Exercise Capacity in Healthy, Active Young Men and Women with Normal GH-Insulin-Like Growth Factor I Axes. J Clin Endocrinol Metab 2005; 90: 3268-73. TABLES AND FIGURES Figure 1. Graphic representation of 22 kDa growth hormone molecule. Figure 2. Pictorial representation of Growth Hormone secretion and regulation. Figure 3. Pictorial representation of IGF-I regulation and action Figure 5. Long-term Effects of GH Replacement Endocrinol Metab 1999;84:2373-2380) Figure 6. Long-term Effects of GH Replacement on Bone. (ter Maaten, J. 1999;84:2373-2380) Figure 7. Long-term Effects of GH Replacement on Cardiac Function. Endocrinol Metab 1999;84:2373-2380)

Girls probably won’t need much

steroids

in there body. As what I know it has a slow process on

HGH

. Steroids can make a man’s body look more muscular and and they look manly on it. The

testosterone

that is forming in the mans body seems to be the only thing they want. Steroids does have some disadvantage and some advantages depending on how you use some of it like dianabol.

F G2 88:2282-92) Figure 14. Common Adverse Effects of HGH and Sex Steroid (Blackman MR, et al. Growth Hormonand Sex Steroid Administration in Healthy Aged Women and Men. JAMA 2002; 288:2282-92) Figure 15. VO2 max at baseline (B) and after 28 d of treatment in the placebo group and in the low dGH group (0.033 mg/kg/d) and the high dose GH group (0.067 mg/kg/d). (Berggren, A. et al. J Clin E