Long-term Treatment with Growth Hormone Decreases Plasminogen Activator Inhibitor-1 and Tissue Plasminogen Activator in Growth Hormone-deficient Adults

 

PDF Download Buy Article Permissions and Reprints

Summary

The syndrome of growth hormone deficiency (GHD) in adults is associated with premature atherosclerosis, increased cardiovascular mortality, abnormal lipoprotein patterns and abnormal body composition. We have previously shown that GH-deficient adults have increased concentrations of fibrinogen and plasminogen activator inhibitor (PAI-1) activity.

The aim of the present investigation was to study coagulation and fibrinolysis in 17 patients with adult-onset GHD during two years of treatment with recombinant human GH (12 μg/kg body weight/day). The impact of the contemporary changes in metabolic variables and body composition on coagulation and fibrinolysis was studied. The patients received conventional thyroid, adrenal and gonadal hormone replacement therapy.

PAI-1 activity, PAI-1 antigen and tissue plasminogen activator (t-PA) antigen levels decreased during the GH treatment period (p <0.05). The decrease was more pronounced in patients with high pre-treatment levels of the different variables. a2-antiplasmin decreased (p <0.05), while plasminogen was unchanged during two years of GH treatment.

Fibrinogen concentrations tended to decrease after two years of GH treatment (p = 0.06), while the coagulation factors VII and VIII were unchanged, von Willebrand factor demonstrated a transient decrease after 18 months of GH treatment. The coagulation inhibitor, protein C, decreased (p <0.05), while antithrombin was unchanged.

Fasting plasma insulin increased (p <0.01), but blood glucose did not differ after two years of GH treatment. Serum high-density lipoprotein cholesterol, total cholesterol and triglycerides were unaltered. Body fat decreased during the initial GH treatment but was unaltered after two years, while lean body mass increased (p <0.001) and the waist over hip circumference ratio tended to decrease (p = 0.06).

In conclusion, PAI-1 activity, PAI-1 antigen and t-PA antigen decreased during long-term GH treatment. These changes may be a direct effect of GH itself or may be secondary to the favourable changes in body composition. It remains to be seen whether changes in these fibrinolytic variables during rhGH treatment reduces the cardiovascular risk in patients with GHD. The present results suggest that GH plays a role in the regulation of fibrinolysis.

• References

• 1 Johansson J-O, Landin K, Tengbom L, Rosen T, Bengtsson B-A. High fibrinogen and plasminogen activator inhibitor activity in growth hormone-deficient adults. Arterio-scler Thromb 1994; 14: 434-437
  CrossrefPubMedGoogle Scholar
• 2 Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321: 1797-1803
  CrossrefPubMedGoogle Scholar
• 3 Rosen T, Eden S, Larson G, Wilhelmsen L, Bengtsson B-A. Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol 1993; 129: 195-200
  PubMedGoogle Scholar
• 4 Johansson J-O, Fowelin J, Landin K, Lager I, Bengtsson B-A. Growth hormone-deficient adults are insulin-resistant. Metabolism 1995; 44: 1126-1129
  CrossrefPubMedGoogle Scholar
• 5 Markussis V, Beshyah SA, Fisher C, Sharp P, Nicolaides AN, Johnston DG. Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults. Lancet 1992; 340: 1188-1192
  CrossrefPubMedGoogle Scholar
• 6 Rosen T, Bengtsson B-A. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990; 336: 285-288
  CrossrefPubMedGoogle Scholar
• 7 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9
  CrossrefPubMedGoogle Scholar
• 8 Vague P, Juhan-Vague I, Aillaud MF, Badier C, Viard R, Alessi MC, Collen D. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects. Metabolism 1986; 35: 250-253
  CrossrefPubMedGoogle Scholar
• 9 Landin K, Tengborn L, Smith U. Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med 1990; 227: 273-278
  CrossrefPubMedGoogle Scholar
• 10 Landin K, Stigendal L, Eriksson E, Krotkiewski M, Risberg B, Tengborn L, Smith U. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. Metabolism 1990; 39: 1044-1048
  CrossrefPubMedGoogle Scholar
• 11 Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501-505
  CrossrefPubMedGoogle Scholar
• 12 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. JAMA 1987; 258: 1183-1186
  CrossrefPubMedGoogle Scholar
• 13 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 2: 533-537
  CrossrefPubMedGoogle Scholar
• 14 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-1168
  CrossrefPubMedGoogle Scholar
• 15 Fowkes FGR, Lowe GDO, Housley E, Rattray A, Rumley A, Elton RA, MacGregor IR, Dawes J. Cross-linked fibrin degradation products, progression of peripheral arterial disease, and risk of coronary heart disease. Lancet 1993; 342: 84-86
  CrossrefPubMedGoogle Scholar
• 16 Chandler WL, Stratton JR. Laboratory evaluation of fibrinolysis in patients with a history of myocardial infarction. Am J Clin Pathol 1994; 102: 248-252
  CrossrefPubMedGoogle Scholar
• 17 Bengtsson B-A, Eden S, Lonn L, Kvist H, Stokland A, Lindstedt G, Bosaeus I, Tolli J, Sjostrom L, Isaksson OGP. Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 1993; 76: 309-317
  PubMedGoogle Scholar
• 18 Eden S, Wiklund O, Oscarsson J, Rosen T, Bengtsson B-A. Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations. Arterioscler Thromb 1993; 13: 296-301
  CrossrefPubMedGoogle Scholar
• 19 Rosen T, Johannsson G, Hallgren P, Caidahl K, Bosaeus I, Bengtsson B-A. Beneficial effects of 12 months replacement therapy with recombinant human growth hormone to growth hormone deficient adults. Endocrinol Metab 1994; 1: 55-66
  PubMedGoogle Scholar
• 20 Caidahl K, Eden S, Bengtsson B-A. Cardiovascular and renal effects of growth hormone. Clin Endocrinol 1994; 40: 393-400
  PubMedGoogle Scholar
• 21 Sarji KE, Levine JH, Nair RMG, Sagel J, Colwell JA. Relation between growth hormone levels and von Willebrand factor activity. J Clin Endo-crinol Metab 1977; 45: 853-856
  CrossrefPubMedGoogle Scholar
• 22 Borkenstein M, Muntean W. Effects of growth hormone on the factor VIII complex in patients with growth hormone deficiency. Metabolism 1984; 33: 1065-1067
  CrossrefPubMedGoogle Scholar
• 23 Ingerslev J, Christensen PD, Stenbjerg S, Møller N, Ørskov H, Christiansen JS. Diabetes-like alterations in hemostatic parameters after growth hormone administration for one week in normal man. J Diabetic Complications 1989; 3: 103-106
  CrossrefPubMedGoogle Scholar
• 24 Jdrgensen JOL, Pedersen SA, Ingerslev J, Møller J, Skakkebaek NE, Christiansen JS. Growth hormone (GH) therapy in GH-deficient patients, the plasma Factor VIII-von Willebrand factor complex, and capillary fragility. A double-blind, placebo-controlled crossover study. Scand J Clin Lab Invest 1990; 50: 417-420
  PubMedGoogle Scholar
• 25 Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosen T, Lindstedt G, Lundberg P-A, Bengtsson B-A. Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clin Endocrinol 1994; 41: 351-357
  CrossrefPubMedGoogle Scholar
• 26 Mazess RB, Barden HS, Bisek JP, Hanson J. Dual-energy x-ray absorptiometry for total-body and regional bone-mineral and soft-tissue composition. Am J Clin Nutr 1990; 51: 1106-1112
  CrossrefPubMedGoogle Scholar
• 27 Nilsson IM, Olow B. Determination of fibrinogen and fibrinogenolytic activity. Thromb Diathes Haemorrh 1962; 8: 297-310
  PubMedGoogle Scholar
• 28 Friberger P, Knos M, Gustavsson S, Aurell L, Claeson G. Methods for determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 1978; 7: 138-145
  PubMedGoogle Scholar
• 29 Padayatty SJ, Orme S, Zenobi PD, Stickland MH, Belchetz PE, Grant PJ. The effects of insulin-like growth factor-1 on plasminogen activator inhibitor-1 synthesis and secretion: results from in vitro and in vivo studies. Thromb Haemost 1993; 70: 1009-1013
  Article in Thieme ConnectPubMedGoogle Scholar
• 30 Heinrich J, Dirkes-Kersting A, Schulte H, Assmann G. Effects of age, menopause and human growth hormone on variables of fibrinolysis. Fibrinolysis 1992; 6 (Suppl. 03) 33-35
  PubMedGoogle Scholar
• 31 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387
  CrossrefPubMedGoogle Scholar
• 32 Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. J Clin Invest 1996; 97: 37-46
  CrossrefPubMedGoogle Scholar
• 33 Laiho M, Saksela O, Andreasen PA, Keski-Oja J. Enhanced production and extracellular deposition of the endothelial-type plasminogen activator inhibitor in cultured human lung fibroblasts by transforming growth factor-β. J Cell Biol 1986; 103: 2403-2410
  CrossrefPubMedGoogle Scholar
• 34 Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-a, and transforming growth factor-β. J Clin Invest 1991; 88: 1346-1353
  PubMedGoogle Scholar
• 35 Fowelin J, Attvall S, Lager I, Bengtsson B-A. Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism 1993; 42: 1443-1447
  CrossrefPubMedGoogle Scholar
• 36 Sundell IB, Nilsson TK, Hallmans G, Hellsten G, Dahlen GH. Interrela-tionships between plasma levels of plasminogen activator inhibitor, tissue plasminogen activator, lipoprotein (a), and established cardiovascu-lar risk factors in a North Swedish population. Atherosclerosis 1989; 80: 9-16
  CrossrefPubMedGoogle Scholar
• 37 Potter van LoonBJ, Kluft C, Radder JK, Blankenstein MA, Meinders AE. The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. Metabolism 1993; 42: 945-949
  CrossrefPubMedGoogle Scholar
• 38 Andersen P, Seljeflot I, Abdelnoor M, Amesen H, Dale PO, Løvik A, Birkeland K. Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome. Metabolism 1995; 44: 611-616
  CrossrefPubMedGoogle Scholar
• 39 Aimer L-O, Nilsson IM. On fibrinolysis in diabetes mellitus. Acta Med Scand 1975; 198: 101-106
  PubMedGoogle Scholar
• 40 Vague P, Juhan-Vague I, Chabert V, Alessi MC, Atlan C. Fat distribution and plasminogen activator inhibitor activity in nondiabetic obese women. Metabolism 1989; 38: 913-915
  CrossrefPubMedGoogle Scholar
• 41 Landin K, Lonnroth P, Krotkiewski M, Holm G, Smith U. Increased insulin resistance and fat cell lipolysis in obese but not lean women with a high waist/hip ratio. Eur J Clin Invest 1990; 20: 530-535
  CrossrefPubMedGoogle Scholar
• 42 Sundell IB, Dahlgren S, Ranby M, Lundin E, Stenling R, Nilsson TK. Reduction of elevated plasminogen activator inhibitor levels during modest weight loss. Fibrinolysis 1989; 3: 51-53
  PubMedGoogle Scholar
• 43 Folsom AR, Qamhieh HT, Wing RR, Jeffery RW, Stinson VL, Kuller LH, Wu KK. Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults. Arterioscler Thromb 1993; 13: 162-169
  CrossrefPubMedGoogle Scholar
• 44 Savendahl LSG, Grankvist K, Engstrom KG. Growth hormone deficiency impairs blood clotting and reduces factor VII coagulant activity in rat. Thromb Haemost 1995; 73: 626-629
  Article in Thieme ConnectPubMedGoogle Scholar
• 45 Negrev N, Nyagolov Y, Stanchewa E. Somatotropin and somatostatin effects on vitamin K-dependent plasma coagulation factors. Eur J Pharmacol 1995; 277: 145-149
  CrossrefPubMedGoogle Scholar