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Impact of HIV on the Hypothalamic-Pituitary Hormonal Axis

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Pituitary Disorders throughout the Life Cycle

Abstract

The human immunodeficiency virus (HIV) and antiretroviral therapy (ART) have well-established effects on the pituitary-growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis. GH dysregulation likely contributes to the complex defects in energy and lipid metabolism characteristic of persons living with HIV (PLWH). The etiology of GH axis abnormalities is likely multifactorial. Several studies have demonstrated decreased pulse amplitude of GH secretion, associated with increased visceral fat characteristic of HIV-associated dyslipidemic lipodystrophy (HADL). Increased somatostatin tone, decreased ghrelin levels, and direct suppression of GH by elevated free fatty acids have been proposed as mechanisms of the GH secretory defect in patients with HIV. The diagnosis of GH deficiency in patients is challenging due to difficulties in interpreting diagnostic tests in the context of HIV infection and obesity. Several therapies have been proposed for GH deficiency coupled with metabolic disturbances in HIV-infected patients. Tesamorelin, a growth hormone-releasing hormone analog, has been approved for use in the USA. Other therapies, including recombinant human growth hormone (r-hGH) and IGF-1 with insulin-like growth factor-binding protein 3 (IGFBP3), have also been proposed. More detailed understanding of the pathophysiology and treatment of defective GH regulation is needed for innovative and practical treatment of the metabolic defects in PLWH.

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References

  1. Sekhar R, Balasubramanyam A. Chapter 43 – Special patient populations: HIV patients. In: Ballantyne CM, editor. Clinical lipidology: a companion to Braunwald’s heart disease. W.B. Saunders; 2009. p. 519–29.

    Chapter  Google Scholar 

  2. Koutkia P, Canavan B, Breu J, Grinspoon S. Growth hormone (GH) responses to GH-releasing hormone-arginine testing in human immunodeficiency virus lipodystrophy. J Clin Endocrinol Metab. 2005;90(1):32–8. https://doi.org/10.1210/jc.2004-1342. Epub 2004 Oct 13. PMID: 15483073.

    Article  CAS  PubMed  Google Scholar 

  3. Debroy P, Feng H, Miao H, Milic J, Ligabue G, Draisci S, Besutti G, Carli F, Menozzi M, Mussini C, Guaraldi G, Lake JE. Changes in central adipose tissue after switching to integrase inhibitors. HIV Res Clin Pract. 2020;21(6):168–73.

    Article  CAS  Google Scholar 

  4. Balasubramanyam A, Sekhar RV, Jahoor F, Jones PH, Pownall HJ. Pathophysiology of dyslipidemia and increased cardiovascular risk in HIV lipodystrophy: a model of 'systemic steatosis'. Curr Opin Lipidol. 2004;15(1):59–67. https://doi.org/10.1097/00041433-200402000-00011. PMID: 15166810.

    Article  CAS  PubMed  Google Scholar 

  5. Rietschel P, Hadigan C, Corcoran C, Stanley T, Neubauer G, Gertner J, Grinspoon S. Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy. J Clin Endocrinol Metab. 2001;86(2):504–10. https://doi.org/10.1210/jcem.86.2.7175. PMID: 11158000.

    Article  CAS  PubMed  Google Scholar 

  6. Koutkia P, Meininger G, Canavan B, Breu J, Grinspoon S. Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy. Am J Physiol Endocrinol Metab. 2004;286(2):E296–303. https://doi.org/10.1152/ajpendo.00335.2003. Epub 2003 Oct 14. PMID: 14559725.

    Article  CAS  PubMed  Google Scholar 

  7. Jessup SK, Dimaraki EV, Symons KV, Barkan AL. Sexual dimorphism of growth hormone (GH) regulation in humans: endogenous GH-releasing hormone maintains basal GH in women but not in men. J Clin Endocrinol Metab. 2003;88(10):4776–80. https://doi.org/10.1210/jc.2003-030246. PMID: 14557454.

    Article  CAS  PubMed  Google Scholar 

  8. Jaffe CA, Ocampo-Lim B, Guo W, Krueger K, Sugahara I, DeMott-Friberg R, Bermann M, Barkan AL. Regulatory mechanisms of growth hormone secretion are sexually dimorphic. J Clin Invest. 1998;102(1):153–64. https://doi.org/10.1172/JCI2908. PMID: 9649569; PMCID: PMC509077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Koutkia P, Eaton K, You SM, Breu J, Grinspoon S. Growth hormone secretion among HIV infected patients: effects of gender, race and fat distribution. AIDS. 2006;20(6):855–62. https://doi.org/10.1097/01.aids.0000218549.85081.8f. PMID: 16549969.

    Article  CAS  PubMed  Google Scholar 

  10. Stanley TL, Grinspoon SK. GH/GHRH axis in HIV lipodystrophy. Pituitary. 2009;12(2):143–52. https://doi.org/10.1007/s11102-008-0092-8. PMID: 18270841.

    Article  CAS  PubMed  Google Scholar 

  11. Falutz J. Growth hormone and HIV infection: contribution to disease manifestations and clinical implications. Best Pract Res Clin Endocrinol Metab. 2011;25(3):517–29. https://doi.org/10.1016/j.beem.2010.11.001. PMID: 21663844.

    Article  CAS  PubMed  Google Scholar 

  12. Zirilli L, Orlando G, Carli F, Madeo B, Cocchi S, Diazzi C, Carani C, Guaraldi G, Rochira V. GH response to GHRH plus arginine is impaired in lipoatrophic women with human immunodeficiency virus compared with controls. Eur J Endocrinol. 2012;166(3):415–24. https://doi.org/10.1530/EJE-11-0829. Epub 2011 Dec 21. PMID: 22189998.

    Article  CAS  PubMed  Google Scholar 

  13. Vahl N, Jorgensen JO, Skjaerbaek C, Veldhuis JD, Orskov H, Christiansen JS. Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults. Am J Physiol. 1997;272:E1108–16. 19.

    CAS  PubMed  Google Scholar 

  14. Veldhuis JD, Cosma M, Erickson D, et al. Tripartite control of growth hormone secretion in women during controlled estradiol repletion. J Clin Endocrinol Metab. 2007;92:2336–45. 20.

    Article  CAS  Google Scholar 

  15. Pijl H, Langendonk JG, Burggraaf J, et al. Altered neuroregulation of GH secretion in viscerally obese premenopausal women. J Clin Endocrinol Metab. 2001;86:5509–15.

    Article  CAS  Google Scholar 

  16. Clasey JL, Weltman A, Patrie J, et al. Abdominal visceral fat and fasting insulin are important predictors of 24-hour GH release independent of age, gender, and other physiological factors. J Clin Endocrinol Metab. 2001;86:3845–52.

    Article  CAS  Google Scholar 

  17. Alvarez CV, Mallo F, Burguera B, Cacicedo L, Dieguez C, Casanueva FF. Evidence for a direct pituitary inhibition by free fatty acids of in vivo growth hormone responses to growth hormone-releasing hormone in the rat. Neuroendocrinology. 1991;53:185–9.

    Article  CAS  Google Scholar 

  18. Perez FR, Camina JP, Zugaza JL, Lage M, Casabiell X, Casanueva FF. cis-FFA do not alter membrane depolarization but block Ca2+ influx and GH secretion in KCl-stimulated somatotroph cells. Suggestion for a direct cis-FFA perturbation of the Ca2+ channel opening. Biochim Biophys Acta. 1997;1329:269–77.

    Article  CAS  Google Scholar 

  19. Maccario M, Procopio M, Loche S, Cappa M, Martina V, Camanni F, Ghigo E. Interaction of free fatty acids and arginine on growth hormone secretion in man. Metabolism. 1994;43(2):223–6. https://doi.org/10.1016/0026-0495(94)90249-6. PMID: 8121306.

    Article  CAS  PubMed  Google Scholar 

  20. Cordido F, Alvarez-Castro P, Isidro ML, Casanueva FF, Dieguez C. Comparison between insulin tolerance test, growth hormone (GH)-releasing hormone (GHRH), GHRH plus acipimox and GHRH plus GH-releasing peptide-6 for the diagnosis of adult GH deficiency in normal subjects, obese and hypopituitary patients. Eur J Endocrinol. 2003;149(2):117–22. https://doi.org/10.1530/eje.0.1490117. PMID: 12887288.

    Article  CAS  PubMed  Google Scholar 

  21. Maccario M, Procopio M, Grottoli S, Oleandri SE, Boffano GM, Taliano M, Camanni F, Ghigo E. Effects of acipimox, an antilipolytic drug, on the growth hormone (GH) response to GH-releasing hormone alone or combined with arginine in obesity. Metabolism. 1996;45(3):342–6. https://doi.org/10.1016/s0026-0495(96)90288-7. PMID: 8606641.

    Article  CAS  PubMed  Google Scholar 

  22. Corneli G, Di Somma C, Baldelli R, Rovere S, Gasco V, Croce CG, Grottoli S, Maccario M, Colao A, Lombardi G, Ghigo E, Camanni F, Aimaretti G. The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index. Eur J Endocrinol. 2005;153(2):257–64. https://doi.org/10.1530/eje.1.01967. PMID: 16061832.

    Article  CAS  PubMed  Google Scholar 

  23. Gasco V, Corneli G, Rovere S, Croce C, Beccuti G, Mainolfi A, Grottoli S, Aimaretti G, Ghigo E. Diagnosis of adult GH deficiency. Pituitary. 2008;11(2):121–8. https://doi.org/10.1007/s11102-008-0110-x. PMID: 18404387.

    Article  CAS  PubMed  Google Scholar 

  24. Brigante G, Diazzi C, Ansaloni A, Zirilli L, Orlando G, Guaraldi G, Rochira V. Gender differences in GH response to GHRH+ARG in lipodystrophic patients with HIV: a key role for body fat distribution. Eur J Endocrinol. 2014;170(5):685–96. https://doi.org/10.1530/EJE-13-0961. PMID: 24536088.

    Article  CAS  PubMed  Google Scholar 

  25. Rochira V, Guaraldi G. Growth hormone deficiency and human immunodeficiency virus. Best Pract Res Clin Endocrinol Metab. 2017;31(1):91–111. https://doi.org/10.1016/j.beem.2017.02.006. Epub 2017 Feb 24. PMID: 28477736.

    Article  CAS  PubMed  Google Scholar 

  26. Coll B, Parra S, Alonso-Villaverde, et al. HIV-infected patients with lipodystrophy have higher rates of carotid atherosclerosis: the role of monocyte chemoattractant protein-1. Cytokine. 2006;34:51–5.

    Article  CAS  Google Scholar 

  27. Lorenz M, Markus H, Bots M, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115:459–67.

    Article  Google Scholar 

  28. Burgess E, Wanke C. Use of recombinant human growth hormone in HIV-associated lipodystrophy. Curr Opin Infect Dis. 2005;18(1):17–24. https://doi.org/10.1097/00001432-200502000-00004. PMID: 15647695.

    Article  CAS  PubMed  Google Scholar 

  29. D'Amico S, Shi J, Sekhar RV, Jahoor F, Ellis KJ, Rehman K, Willis J, Maldonado M, Balasubramanyam A. Physiologic growth hormone replacement improves fasting lipid kinetics in patients with HIV lipodystrophy syndrome. Am J Clin Nutr. 2006;84(1):204–11. https://doi.org/10.1093/ajcn/84.1.204. PMID: 16825697.

    Article  CAS  PubMed  Google Scholar 

  30. Leung VL, Glesby MJ. Pathogenesis and treatment of HIV lipohypertrophy. Curr Opin Infect Dis. 2011;24(1):43–9. https://doi.org/10.1097/QCO.0b013e3283420eef. PMID: 21124215; PMCID: PMC3671942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gelato M, McNurlan M, Freedland E. Role of recombinant human growth hormone in HIV-associated wasting and cachexia: pathophysiology and rationale for treatment. Clin Ther. 2007;29(11):2269–88. https://doi.org/10.1016/j.clinthera.2007.11.004. PMID: 18158071.

    Article  CAS  PubMed  Google Scholar 

  32. Lo J, You SM, Canavan B, Liebau J, Beltrani G, Koutkia P, Hemphill L, Lee H, Grinspoon S. Low-dose physiological growth hormone in patients with HIV and abdominal fat accumulation: a randomized controlled trial. JAMA. 2008;300(5):509–19. https://doi.org/10.1001/jama.300.5.509. PMID: 18677023; PMCID: PMC2532757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mauras N, O'Brien KO, Welch S, Rini A, Helgeson K, Vieira NE, Yergey AL. Insulin-like growth factor I and growth hormone (GH) treatment in GH-deficient humans: differential effects on protein, glucose, lipid, and calcium metabolism. J Clin Endocrinol Metab. 2000;85(4):1686–94. https://doi.org/10.1210/jcem.85.4.6541. PMID: 10770216.

    Article  CAS  PubMed  Google Scholar 

  34. Rao MN, Mulligan K, Tai V, Wen MJ, Dyachenko A, Weinberg M, Li X, Lang T, Grunfeld C, Schwarz JM, Schambelan M. Effects of insulin-like growth factor (IGF)-I/IGF-binding protein-3 treatment on glucose metabolism and fat distribution in human immunodeficiency virus-infected patients with abdominal obesity and insulin resistance. J Clin Endocrinol Metab. 2010;95(9):4361–6. https://doi.org/10.1210/jc.2009-2502. Epub 2010 Jul 7. PMID: 20610601; PMCID: PMC2936071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Falutz J, Allas S, Blot K, Potvin D, Kotler D, Somero M, Berger D, Brown S, Richmond G, Fessel J, Turner R, Grinspoon S. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007;357(23):2359–70. https://doi.org/10.1056/NEJMoa072375. PMID: 18057338.

    Article  CAS  PubMed  Google Scholar 

  36. Stanley TL, Falutz J, Mamputu JC, Soulban G, Potvin D, Grinspoon SK. Effects of tesamorelin on inflammatory markers in HIV patients with excess abdominal fat: relationship with visceral adipose reduction. AIDS. 2011;25(10):1281–8. https://doi.org/10.1097/QAD.0b013e328347f3f1. PMID: 21516030; PMCID: PMC3673013.

    Article  CAS  PubMed  Google Scholar 

  37. Mangili A, Falutz J, Mamputu JC, Stepanians M, Hayward B. Predictors of treatment response to tesamorelin, a growth hormone-releasing factor analog, in HIV-infected patients with excess abdominal fat. PLoS One. 2015;10(10):e0140358. https://doi.org/10.1371/journal.pone.0140358. PMID: 26457580; PMCID: PMC4601733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Falutz J, Potvin D, Mamputu JC, Assaad H, Zoltowska M, Michaud SE, Berger D, Somero M, Moyle G, Brown S, Martorell C, Turner R, Grinspoon S. Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension. J Acquir Immune Defic Syndr. 2010;53(3):311–22. https://doi.org/10.1097/QAI.0b013e3181cbdaff. PMID: 20101189.

    Article  CAS  PubMed  Google Scholar 

  39. Stanley TL, Feldpausch MN, Oh J, Branch KL, Lee H, Torriani M, Grinspoon SK. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial. JAMA. 2014;312(4):380–9. https://doi.org/10.1001/jama.2014.8334. PMID: 25038357; PMCID: PMC4363137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Stanley TL, Falutz J, Marsolais C, Morin J, Soulban G, Mamputu JC, Assaad H, Turner R, Grinspoon SK. Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin. Clin Infect Dis. 2012;54(11):1642–51. https://doi.org/10.1093/cid/cis251. Epub 2012 Apr 10. PMID: 22495074; PMCID: PMC3348954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sekhar RV, Balasubramanyam A. Treatment of dyslipidemia in HIV-infected patients. Expert Opin Pharmacother. 2010;11(11):1845–54. https://doi.org/10.1517/14656566.2010.487484. PMID: 20486828.

    Article  CAS  PubMed  Google Scholar 

  42. Agarwal N, Iyer D, Patel SG, Sekhar RV, Phillips TM, Schubert U, Oplt T, Buras ED, Samson SL, Couturier J, Lewis DE, Rodriguez-Barradas MC, Jahoor F, Kino T, Kopp JB, Balasubramanyam A. HIV-1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co-regulation. Sci Transl Med. 2013;5(213):213ra164. https://doi.org/10.1126/scitranslmed.3007148. PMID: 24285483; PMCID: PMC4009012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Grunfeld C, Thompson M, Brown SJ, Richmond G, Lee D, Muurahainen N, Kotler DP, Study 24380 Investigators Group. Recombinant human growth hormone to treat HIV-associated adipose redistribution syndrome: 12 week induction and 24-week maintenance therapy. J Acquir Immune Defic Syndr. 2007;45(3):286–97. https://doi.org/10.1097/QAI.0b013e3180691145. PMID: 17592343.

    Article  CAS  PubMed  Google Scholar 

  44. Lo J, You SM, Liebau J, Lee H, Grinspoon S. Effects of low-dose growth hormone withdrawal in patients with HIV. JAMA. 2010;304(3):272–4. https://doi.org/10.1001/jama.2010.989. PMID: 20639560; PMCID: PMC3204609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Waters D, Danska J, Hardy K, et al. Recombinant human growth hormone, insulin-like growth factor 1, and combination therapy in AIDS associated wasting. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1996;125:865–72.

    Article  CAS  Google Scholar 

  46. Ellis KJ, Lee PD, Pivarnik JM, et al. Changes in body composition of human immunodeficiency virus infected males receiving insulin like growth factor I and growth hormone. J Clin Endocrinol Metab. 1996;81:3033–8.

    CAS  PubMed  Google Scholar 

  47. Lee PD, Pivarnik JM, Bukar JG, et al. A randomized, placebo-controlled trial of combined insulin-like growth factor I and low dose growth hormone therapy for wasting associated with human immunodeficiency virus infection [published correction appears in J Clin Endocrinol Metab. 1996;81: 3696]. J Clin Endocrinol Metab. 1996;81:2968–75.

    CAS  PubMed  Google Scholar 

  48. Leung V, Chiu YL, Kotler DP, Albu J, Zhu YS, Ham K, Engelson ES, Hammad H, Christos P, Donovan DS, Ginsberg HN, Glesby MJ. Effect of recombinant human growth hormone and rosiglitazone for HIV-associated abdominal fat accumulation on adiponectin and other markers of inflammation. HIV Clin Trials. 2016;17(2):55–62. https://doi.org/10.1080/15284336.2015.1126424. Epub 2016 Feb 1. PMID: 27077672; PMCID: PMC4941209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Glesby MJ, Albu J, Chiu YL, Ham K, Engelson E, He Q, Muthukrishnan V, Ginsberg HN, Donovan D, Ernst J, Lesser M, Kotler DP. Recombinant human growth hormone and rosiglitazone for abdominal fat accumulation in HIV-infected patients with insulin resistance: a randomized, double-blind, placebo-controlled, factorial trial. PLoS One. 2013;8(4):e61160. https://doi.org/10.1371/journal.pone.0061160. PMID: 23593417; PMCID: PMC3625151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Falutz J, Allas S, Mamputu JC, Potvin D, Kotler D, Somero M, Berger D, Brown S, Richmond G, Fessel J, Turner R, Grinspoon S. Long-term safety and effects of tesamorelin, a growth hormone-releasing factor analogue, in HIV patients with abdominal fat accumulation. AIDS. 2008;22(14):1719–28. https://doi.org/10.1097/QAD.0b013e32830a5058. PMID: 18690162.

    Article  CAS  PubMed  Google Scholar 

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Kikani, N., Balasubramanyam, A. (2022). Impact of HIV on the Hypothalamic-Pituitary Hormonal Axis. In: Samson, S.L., Ioachimescu, A.G. (eds) Pituitary Disorders throughout the Life Cycle. Springer, Cham. https://doi.org/10.1007/978-3-030-99918-6_28

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