A partir de la década de los ochenta comenzó la disponibilidad clínica de GH humana obtenida a partir de tecnología de DNA recombinante (1). Desde entonces se comenzó el empleo terapéutico de esta hormona en pacientes adultos con deficiencia de GH obteniéndose resultados altamente favorables en lo que se refiere a la corrección de anomalías metabólicas y trastornos de la composición corporal que presentan los pacientes con esta deficiencia hormonal (2-3-4-5-6-7-8-9). En síntesis, en estos pacientes, el tratamiento c o n GH exógena produce un aumento de la masa magra, reducción de la masa adiposa, aumento de v o l u m e n y fuerza musculares y reducción del cociente cintura-cadera. El aumento de la tasa metabólica basal se acompaña de un incremento de la retención nitrogenada. El aumento de la lipolisis inducido por la GH se asocia a un incremento de las concentraciones de ácidos grasos libres y reducción del colesterol sérico. El efecto antiinsulinoide de la GH se traduce en una reducción de la tolerancia a la glucosa. El tratamiento con GH se acompaña, además, de una mejoría en las alteraciones psicológicas que con frecuencia acompañan a la deficiencia de GH. Los pacientes tratados con GH refieren en muchas ocasiones un aumento de la sensación de bienestar evaluada mediante diversas pruebas psicométricas. La fuerza muscular y la capacidad para el ejercicio también se incrementan, con lo que globalmente se consigue una mejoría en la calidad de vida (10). Pero no quedan ahí las posibilidades terapéuticas de esta hormona en pacientes adultos. En efecto, la administración de GH exógena como factor anabolizante ha demostrado su eficacia terapéutica en diversas situaciones clínicas caracterizadas por un estado catabólico severo. Las propiedades anabolizantes de la GH se han demostrado en situaciones tales como quemaduras (11-12), sepsis (13), cirugía (14-15-16), síndrome de inmunodeficiencia adquirida (17). Otras situaciones no deficitarias en las que se ha ensayado el tratamiento con GH recombinante han sido los trastornos gonadales y de la fertilidad (18-19-20), la osteoporosis (21-22-23), la enferrnedad pulmonar obstructiva crónica (24-25) y como coadyuvante en el tratamiento de úlceras diabéticas (26), obesidad (27-28) y en pacientes sometidos a nutrición parenteral (29-30). Se ha empleado también GH en un intento de incrementar el rendimiento atlético (31) y como agente inmunomodulador. En todas estas situaciones la terapia con GH ha mostrado un favorecimiento del anabolismo proteico, una disminución del catabolismo proteico, una acción lipolítica y, en muchas ocasiones, una sustancial mejoría clínica de los pacientes.
BIBLIOGRAFIA
1. Goeddel DV, Heynecker HL, Hozumi T, Arentzen R, Itakura K, Yansura DG, Ross MR, Miozzari G, Crea R y Seeburg PH: Direct expression in Escherichia coli of a DNA sequence cod i n g for human growth hormone. Nature 2 8 1 : 5 4 4 - 5 4 8 , 1979.
2. Grumbach MM: Growth hormone therapy and the short end of the stick. N Engl J Med 319:238-241, 1988.
3. Jørgensen JOL, Pedersen SA, Thuesen L, Jørgensen J, Ingemann-Hasen T, Skakkebaek NE y Christiansen JS: Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 1:1221-1225, 1989.
4. Salomon F, Cuneo RC, Hesp R y Sonksen PH: The effects of t r e a t m e n t with recombinant human growth hormone on b o d y composition and metabolism in adults with growth hormone deficiency. N Engl J Med 321:1707-1803, 1989.
5. Whitehead HM, Boreham C, McIlrath EM, Sheridan B, Kennedy L, Atkinson AB y Hadden DR: Growth hormone treatment of adults with growth hormone deficiency: results of a 13-month placebo controlled cross-over study. Clin Endocrinol (Oxford) 36:45-52, 1992.
6. B i n n e r t s A, Swart GR, Wilson JHP, Hoogerbrugge N, Pols HAP, Birkenhager JC y Lamberts SWJ: The effect of growth hormone administration in growth hormone deficient adults o n bone, protein, carbohydrate and lipid homeostasis, as w e l l as on body composition. Clin Endocrinol ( O x f o r d ) 37:79-87, 1992.
7. Degerblad M, Elgindy N, Hall K, Sjoberg HE y Thoren M: Potent effect of recombinant growth hormone on bone mineral density and body composition in adults with panhypopituitarism. Acta Endocrinol (Copenh) 126:387-393, 1992.
8. O r m e SM, Sebastian JP, Oldroyd B, Stewart SP, Grant PJ, Stickland MH, Smith MA y Belchetz PE: Comparison of measures of body composition in a trial of low dose growth horm o n e replacement therapy. Clin Endocrinol ( O x f o r d ) 37:453-459, 1992.
9. O ' H a l l o r a n DJ, Tsatsoulis A, Whitehouse RW, Holmes SJ, Adams JE y Shalet SM: Increased bone density after recombin a n t human growth hormone (GH) therapy in adults with isolated GH deficiency. J Clin Endocrinol Metab 76:13441348, 1993.
10. Díez JJ y Gómez-Pan A: Nuevos aspectos fisiológicos y farmacológicos de la hormona del crecimiento (I). Efectos en adultos. Rev Clín Esp 192:280-287, 1993.
11. Liljedahl SO, Gemzell CA, Plantin LO y Birke G: Effect of human growth hormone in patients with severe burns. Acta Chir Scand 122:1-14, 1961.
12. S o r o f f HS, Pearson H, Green NL y Artz CP: The effect of growth hormone on nitrogen balance at various levels of intake in burned patients. Surg Gynecol Obstet 111:259-273, 1960.
13. Voerman HJ, Strack van Schijndel RJ, Groeneveld AB, de Boer H, Nauta JP, van der Veen EA y Thijs LG: Effects of recombinant human growth hormone in patients with severe sepsis.
14. Ann Surg 216:648-655, 1992. Ward HC, Halliday D y Sim AJW: Protein and energy metabolism with biosynthetic human growth hormone after gastrointestinal surgery. Ann Surg 206:56-61, 1987.
15. Mjaaland M, Unnenberg K, Hotvedt R y Revhaug A: Nitrogen retention caused by growth hormone in patients undergoing gastrointestinal surgery with epidural analgesia and parenteral nutrition. Eur J Surg 157:21-27, 1991.
16. Pointing GA, Halliday D, Teale JD y Sim AJW: Postoperative positive nitrogen balance with intravenous hyponutrition and growth hormone. Lancet 1:438-440, 1988. Mulligan K, Grunfeld C, Hellerstein MK, Neese RA y Schamb e l a n M:
17. Anabolic effects of recombinant human growth hormone in patients with wasting associated with human imm u n o d e f i c i e n c y virus infection. J Clin Endocrinol Metab 77:956-962, 1993.
18. Shoham Z, Homburg R, Owen EJ, Conway GS, Ostergaard H y Jacobs HS: The role of treatment with growth hormone in infertile patients. Bailliere's Clin Obstet Gynaecol 6:267281, 1992.
19. B r i n g e r J, Lhoret RR, Hedon B y Lefebvre P: The use of growth hormone (hGH) in ovulation induction in women. Contracept Fertil Sex 21:678-682, 1993.
20. Hillensjo T y Bergh C: Effects of growth hormone on reproduction. Acta Endocrinol (Copenh) 128 (suppl 2):23-25, 1993.
21. Aloia JF, Zanzi I, Ellis K, Jowsey J, Roginsky M, Wallach S y Cohn SH: Effects of growth hormone in osteoporosis. J Clin Endocrinol Metab 43:992-999, 1976.
22. Haas HG, Dambacher MA, Goschke H, Guncaga J, Lauffenburger T, Lentner C, Olah A y Wacker HR: Growth hormone in osteoporosis. Calcif Tissue Res 21:467-468, 1976.
23. Rubin CD: Growth hormone-aging and osteoporosis. Am J Med Sci 305:120-129, 1993.
24. Goldstein SA, Askanazi J, Weissman C, Thomashaw B y Kinney JM: Energy expenditure in malnourished patients with c h r o n i c obstructive pulmonary disease. Chest 9 : 2 2 2 - 2 2 4 , 1987.
25. Suchner U, Rothkopf MM, Stanislaus G, Elwyn DH, Kvetan V y Askanazi J: Growth hormone and pulmonary disease. Metabolic effects in patients receiving parenteral nutrition. Arch Intern Med 150:1225-1230, 1990.
26. Waago H: Local treatment of ulcers in diabetic foot with human growth hormone. Lancet 1:1485, 1987.
27. Bray GA, Raben MS, Londono J y Gallaher TF Jr: Effects of triiodothyronine, growth hormone and anabolic steroids on nitrogen excretion and oxygen consumption of obese patients.
28. J Clin Endocrinol Metab 33:293-300, 1971. Clemmons DR, Snyder DK y Underwood LE: Interaction of growth hormone and nutritional intake in facilitating nitrogen conservation and promoting lipolysis. En Bercu BB, ed. Basic and clinical aspects of growth hormone. New York: Plenum Press, 1988 pp. 347-355.
29. M a n s o n JMcK y Wilmore DW: Positive nitrogen balance with human growth hormone and hypocaloric intravenous feeding. Surgery 100:188-197, 1986.
30. Ma n so n JMcK y Wilmore DW: Use of growth hormone in s u r g e r y . En Bercu BB, ed. Basic and clinical aspects of growth hormone. New York, Plenum Press, 1988, pp. 339346. Manson JMcK, Smith RJ y Wilmore DW: Growth hormone stimulates protein synthesis during hypocaloric parenteral nutrition. Role of hormone-substrate environment. Ann Surg 208:136-142, 1988.
31. Deyssig R, Frisch H, Blum WF y Waldhor T: Effect of growth hormone treatment on hormonal parameters, body composit i o n and strength in athletes. Acta Endocrinol ( C o p e n h ) 128:313-318, 1993.
成人生长激素
自20世纪80年代以来,通过重组DNA技术获取的人类生长激素(GH)已应用于临床(1)。此后,该激素已开始用于治疗患有生长激素缺乏症的成年患者,并在纠正此类激素缺乏症患者的代谢异常和身体成分紊乱方面取得了非常良好的效果(2-3-4-5-6-7-8-9)。总而言之,在这些患者中,外源性生长激素治疗可增加瘦体重,减少脂肪量,增加肌肉体积和力量,并降低腰臀比。基础代谢率的提高伴随着氮潴留的增加。生长激素诱导的脂肪分解增加与游离脂肪酸浓度的升高和血清胆固醇的降低有关。生长激素的抗胰岛素样作用可转化为葡萄糖耐量降低。生长激素治疗还能改善生长激素缺乏症常伴发的心理障碍。接受生长激素 (GH) 治疗的患者通常会报告称,他们的幸福感有所提升,这通过各种心理测试得到评估。肌肉力量和运动能力也得到提升,从而整体改善了生活质量 (10)。然而,这种激素在成年患者中的治疗潜力远不止于此。事实上,外源性生长激素 (GH) 作为合成代谢剂的给药已证明其在各种以严重分解代谢状态为特征的临床情况下均具有治疗效果。GH 的合成代谢特性已在烧伤 (11-12)、脓毒症 (13)、手术 (14-15-16) 和获得性免疫缺陷综合征 (17) 等情况下得到证实。重组生长激素 (GH) 疗法已在其他非缺乏症疾病中得到测试,包括性腺和生育障碍 (18-19-20)、骨质疏松症 (21-22-23)、慢性阻塞性肺病 (24-25),以及作为糖尿病溃疡 (26)、肥胖症 (27-28) 和接受肠外营养 (29-30) 患者的辅助治疗。生长激素 (GH) 也被用于提高运动成绩 (31) 和作为免疫调节剂。在所有这些情况下,生长激素疗法均已证明能够改善蛋白质合成代谢、降低蛋白质分解代谢、增强脂肪分解作用,并且在许多情况下,能够显著改善患者的临床症状。
参考文献
1. Goeddel DV, Heynecker HL, Hozumi T, Arentzen R, Itakura K, Yansura DG, Ross MR, Miozzari G, Crea R y Seeburg PH: Direct expression in Escherichia coli of a DNA sequence cod i n g for human growth hormone. Nature 2 8 1 : 5 4 4 - 5 4 8 , 1979.
2. Grumbach MM: Growth hormone therapy and the short end of the stick. N Engl J Med 319:238-241, 1988.
3. Jørgensen JOL, Pedersen SA, Thuesen L, Jørgensen J, Ingemann-Hasen T, Skakkebaek NE y Christiansen JS: Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 1:1221-1225, 1989.
4. Salomon F, Cuneo RC, Hesp R y Sonksen PH: The effects of t r e a t m e n t with recombinant human growth hormone on b o d y composition and metabolism in adults with growth hormone deficiency. N Engl J Med 321:1707-1803, 1989.
5. Whitehead HM, Boreham C, McIlrath EM, Sheridan B, Kennedy L, Atkinson AB y Hadden DR: Growth hormone treatment of adults with growth hormone deficiency: results of a 13-month placebo controlled cross-over study. Clin Endocrinol (Oxford) 36:45-52, 1992.
6. B i n n e r t s A, Swart GR, Wilson JHP, Hoogerbrugge N, Pols HAP, Birkenhager JC y Lamberts SWJ: The effect of growth hormone administration in growth hormone deficient adults o n bone, protein, carbohydrate and lipid homeostasis, as w e l l as on body composition. Clin Endocrinol ( O x f o r d ) 37:79-87, 1992.
7. Degerblad M, Elgindy N, Hall K, Sjoberg HE y Thoren M: Potent effect of recombinant growth hormone on bone mineral density and body composition in adults with panhypopituitarism. Acta Endocrinol (Copenh) 126:387-393, 1992.
8. O r m e SM, Sebastian JP, Oldroyd B, Stewart SP, Grant PJ, Stickland MH, Smith MA y Belchetz PE: Comparison of measures of body composition in a trial of low dose growth horm o n e replacement therapy. Clin Endocrinol ( O x f o r d ) 37:453-459, 1992.
9. O ' H a l l o r a n DJ, Tsatsoulis A, Whitehouse RW, Holmes SJ, Adams JE y Shalet SM: Increased bone density after recombin a n t human growth hormone (GH) therapy in adults with isolated GH deficiency. J Clin Endocrinol Metab 76:13441348, 1993.
10. Díez JJ y Gómez-Pan A: Nuevos aspectos fisiológicos y farmacológicos de la hormona del crecimiento (I). Efectos en adultos. Rev Clín Esp 192:280-287, 1993.
11. Liljedahl SO, Gemzell CA, Plantin LO y Birke G: Effect of human growth hormone in patients with severe burns. Acta Chir Scand 122:1-14, 1961.
12. S o r o f f HS, Pearson H, Green NL y Artz CP: The effect of growth hormone on nitrogen balance at various levels of intake in burned patients. Surg Gynecol Obstet 111:259-273, 1960.
13. Voerman HJ, Strack van Schijndel RJ, Groeneveld AB, de Boer H, Nauta JP, van der Veen EA y Thijs LG: Effects of recombinant human growth hormone in patients with severe sepsis.
14. Ann Surg 216:648-655, 1992. Ward HC, Halliday D y Sim AJW: Protein and energy metabolism with biosynthetic human growth hormone after gastrointestinal surgery. Ann Surg 206:56-61, 1987.
15. Mjaaland M, Unnenberg K, Hotvedt R y Revhaug A: Nitrogen retention caused by growth hormone in patients undergoing gastrointestinal surgery with epidural analgesia and parenteral nutrition. Eur J Surg 157:21-27, 1991.
16. Pointing GA, Halliday D, Teale JD y Sim AJW: Postoperative positive nitrogen balance with intravenous hyponutrition and growth hormone. Lancet 1:438-440, 1988. Mulligan K, Grunfeld C, Hellerstein MK, Neese RA y Schamb e l a n M:
17. Anabolic effects of recombinant human growth hormone in patients with wasting associated with human imm u n o d e f i c i e n c y virus infection. J Clin Endocrinol Metab 77:956-962, 1993.
18. Shoham Z, Homburg R, Owen EJ, Conway GS, Ostergaard H y Jacobs HS: The role of treatment with growth hormone in infertile patients. Bailliere's Clin Obstet Gynaecol 6:267281, 1992.
19. B r i n g e r J, Lhoret RR, Hedon B y Lefebvre P: The use of growth hormone (hGH) in ovulation induction in women. Contracept Fertil Sex 21:678-682, 1993.
20. Hillensjo T y Bergh C: Effects of growth hormone on reproduction. Acta Endocrinol (Copenh) 128 (suppl 2):23-25, 1993.
21. Aloia JF, Zanzi I, Ellis K, Jowsey J, Roginsky M, Wallach S y Cohn SH: Effects of growth hormone in osteoporosis. J Clin Endocrinol Metab 43:992-999, 1976.
22. Haas HG, Dambacher MA, Goschke H, Guncaga J, Lauffenburger T, Lentner C, Olah A y Wacker HR: Growth hormone in osteoporosis. Calcif Tissue Res 21:467-468, 1976.
23. Rubin CD: Growth hormone-aging and osteoporosis. Am J Med Sci 305:120-129, 1993.
24. Goldstein SA, Askanazi J, Weissman C, Thomashaw B y Kinney JM: Energy expenditure in malnourished patients with c h r o n i c obstructive pulmonary disease. Chest 9 : 2 2 2 - 2 2 4 , 1987.
25. Suchner U, Rothkopf MM, Stanislaus G, Elwyn DH, Kvetan V y Askanazi J: Growth hormone and pulmonary disease. Metabolic effects in patients receiving parenteral nutrition. Arch Intern Med 150:1225-1230, 1990.
26. Waago H: Local treatment of ulcers in diabetic foot with human growth hormone. Lancet 1:1485, 1987.
27. Bray GA, Raben MS, Londono J y Gallaher TF Jr: Effects of triiodothyronine, growth hormone and anabolic steroids on nitrogen excretion and oxygen consumption of obese patients.
28. J Clin Endocrinol Metab 33:293-300, 1971. Clemmons DR, Snyder DK y Underwood LE: Interaction of growth hormone and nutritional intake in facilitating nitrogen conservation and promoting lipolysis. En Bercu BB, ed. Basic and clinical aspects of growth hormone. New York: Plenum Press, 1988 pp. 347-355.
29. M a n s o n JMcK y Wilmore DW: Positive nitrogen balance with human growth hormone and hypocaloric intravenous feeding. Surgery 100:188-197, 1986.
30. Ma n so n JMcK y Wilmore DW: Use of growth hormone in s u r g e r y . En Bercu BB, ed. Basic and clinical aspects of growth hormone. New York, Plenum Press, 1988, pp. 339346. Manson JMcK, Smith RJ y Wilmore DW: Growth hormone stimulates protein synthesis during hypocaloric parenteral nutrition. Role of hormone-substrate environment. Ann Surg 208:136-142, 1988.
31. Deyssig R, Frisch H, Blum WF y Waldhor T: Effect of growth hormone treatment on hormonal parameters, body composit i o n and strength in athletes. Acta Endocrinol ( C o p e n h ) 128:313-318, 1993.