A review of the role of testosterone in the care of the critically ill patient

Main Article Content

R Stevenson
D Bishop
R Rodseth

Abstract





Testosterone is an anabolic and androgenic steroid hormone therapeutically used to produce male sex characteristics. It has also been shown to have a modulating effect on proinflammatory biomarkers. Critical illness is characterised by a proinflammatory and catabolic state and is accompanied by altered testosterone production, which may persist into the recovery phase. Testosterone may, therefore be a potential therapeutic option in critical illness. This paper reviews normal testosterone physiology, and the changes seen during critical illness and systematically reviews testosterone therapy during both the acute and chronic phases of critical illness.





Article Details

How to Cite
A review of the role of testosterone in the care of the critically ill patient. (2024). Southern African Journal of Critical Care, 40(1). https://doi.org/10.7196/SAJCC.2024.v40i1.1303
Section
Review Articles
Author Biographies

D Bishop, Department of Anaesthesia and Critical Care, University of KwaZulu-Natal, Pietermaritzburg, South Africa

Honorary Associate Professor, Department of Anaesthesia and Critical Care, University of KwaZulu-Natal, Pietermaritzburg, South Africa

R Rodseth, Department of Anaesthesia and Critical Care, University of KwaZulu-Natal, Pietermaritzburg, South Africa; Netcare Ltd, Johannesburg, South Africa

Honorary Associate Professor, Department of Anaesthesia and Critical Care, University of KwaZulu-Natal, Pietermaritzburg, South Africa

How to Cite

A review of the role of testosterone in the care of the critically ill patient. (2024). Southern African Journal of Critical Care, 40(1). https://doi.org/10.7196/SAJCC.2024.v40i1.1303

References

Traish A, Bolanos J, Nair S, Saad F, Morgentaler A. Do androgens modulate the pathophysiological pathways of inflammation? Appraising the contemporary evidence. J Clin Med 2018;7(12). https://doi.org/10.3390/jcm7120549

Aghazadeh Y, Zirkin BR, Papadopoulos V. Pharmacological regulation of the cholesterol transport machinery in steroidogenic cells of the testis. Vitamins & Hormones 2015;98:189-227. https://doi. org/10.1016/bs.vh.2014.12.006

Corradi PF, Corradi RB, Greene LW. Physiology of the hypothalamic-pituitary-gonadal axis in the male. Urol Clin North America 2016;43(2):151-162. https://doi.org/10.1016/j.ucl.2016.01.001 4. Baldassarri M, Picchiotti N, Fava F, et al. Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males. E Bio Med 2021;65:103246. https://doi.

org/10.1016/j.ebiom.2021.103246

Davey RA, Grossmann M. Androgen receptor structure, function and biology: From bench to bedside. Clin Biochemist Rev 2016;37(1):3-15.

Foradori CD, Weiser MJ, Handa RJ. Non-genomic actions of androgens. Front Neuroendocrinol 2008;29(2):169-181. https://doi.org/10.1016/j.yfrne.2007.10.005

Kelly DM, Jones TH. Testosterone: a vascular hormone in health and disease. J Endocrinol 2013;217(3):R47-71. https://doi.org/10.1530/joe-12-0582

Van Aerde N, Van Dyck L, Vanhorebeek I, Van den Berghe G. Endocrinopathy of the critically ill. In: Preiser J-C, Herridge M, Azoulay E, editors. Post-intensive care syndrome. Cham: Springer International Publishing; 2020. 125-143.

Christeff N, Benassayag C, Carli-Vielle C, Carli A, Nunez EA. Elevated oestrogen and reduced testosterone levels in the serum of male septic shock patients. J Steroid Biochemistry 1988;29(4):435-440. https://doi.org/10.1016/0022-4731(88)90254-3

Bech A, van Leeuwen H, Telting D, van Borren M, de Boer H. Time course of gonadal hormone profiles in male patients with sepsis. Netherlands J Crit Care 2020;28(6):238-243.

Foster MA, Taylor AE, Hill NE, et al. The Endocrine and metabolic response in male survivors of major trauma. J Clin Endocrine Metabol 2019:577502. https://doi.org/10.1101/577502

Schröder J, Kahlke V, Staubach KH, Zabel P, Stüber F. Gender differences in human sepsis. Arch Surg 1998;133(11):1200-1205. https://doi.org/10.1001/archsurg.133.11.1200

Clausen CL, Holm Johannsen T, Erik Skakkebæk N, et al. Pituitary-gonadal hormones associated with respiratory failure in men and women hospitalised with COVID-19: An observational cohort study. Endocrine Connect 2023;12(1). https://doi.org/10.1530/ec-22-0444

Mechanick JI, Nierman DM. Gonadal steroids in critical illness. Crit Care Clin 2006;22(1):87-103, vii. https://doi.org/10.1016/j.ccc.2005.08.005

Langouche L, Van den Berghe G. The dynamic neuroendocrine response to critical illness. Endocrinol Metabol Clin North Am 2006;35(4):777-791. https://doi.org/10.1016/j.ecl.2006.09.007 16. Ashoka HG, Prakashini MV, Manthappa M, Ashok P. Study of serum testosterone as a prognostic indicator in patients with respiratory failure on mechanical ventilation. Int J health sci

;6(s2):2753-2761. https://doi.org/10.53730/ijhs.v6ns2.5670

Foster MA, Taylor AE, Hill NE, et al. Mapping the steroid response to major trauma from injury

to recovery: A prospective cohort study. J Clin Endocrinol Metabol 2020;105(3):925-937. https://

doi.org/10.1210/clinem/dgz302

Almoosa KF, Gupta A, Pedroza C, Watts NB. Low testosterone levels are frequent in patients with acute respiratory failure and are associated with poor outcomes. Endocrin Prac 2014;20(10):1057- 1063. https://doi.org/10.4158/ep14003.Or

Sahana PK, Ghosh A, Mukhopadhyay P, Pandit K, Chowdhury BR, Chowdhury S. A study on endocrine changes in patients in intensive care unit. J Indian Med Assoc 2008;106(6):362-364. 20. Dhindsa S, Zhang N, McPhaul MJ, et al. Association of circulating sex hormones with inflammation

and disease severity in patients with COVID-19. JAMA Netw Open 2021;4(5):e2111398. https://

doi.org/10.1001/jamanetworkopen.2021.11398

Infante M, Pieri M, Lupisella S, et al. Low testosterone levels and high estradiol to testosterone ratio are associated with hyperinflammatory state and mortality in hospitalised men with COVID-19. Eur Rev Med Pharmacol Sci 2021;25(19):5889-5903. https://doi.org/10.26355/ eurrev_202110_26865

Cai Z, Zhong J, Jiang Y, Zhang J. Associations between COVID-19 infection and sex steroid hormones. Front Endocrinol (Lausanne) 2022;13:940675. https://doi.org/10.3389/ fendo.2022.940675

Leach DA, Brooke GN, Bevan CL. Roles of steroid receptors in the lung and COVID-19. Essays Biochem 2021;65(6):1025-1038. https://doi.org/10.1042/ebc20210005

Al-Lami RA, Urban RJ, Volpi E, Algburi AMA, Baillargeon J. Sex hormones and novel corona virus infectious disease (COVID-19). Mayo Clin Proceedings 2020;95(8):1710-1714. https://doi. org/10.1016/j.mayocp.2020.05.013

Acharjee A, Hazeldine J, Bazarova A, et al. Integration of metabolomic and clinical data improves the prediction of intensive care unit length of stay following major traumatic injury. Metabol 2021;12(1). https://doi.org/10.3390/metabo12010029

Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons from the testosterone trials. Endocr Rev 2018;39(3):369-386. https://doi.org/10.1210/er.2017-00234

Mohler ER III, Ellenberg SS, Lewis CE, et al. The effect of testosterone on cardiovascular biomarkers in the testosterone trials. J Clin Endocrinol Metabol 2018;103(2):681-688. https://doi. org/10.1210/jc.2017-02243

Cai T, Hu Y, Ding B, et al. Effect of metformin on testosterone levels in male patients with type 2 diabetes mellitus treated with insulin. Front Endocrinol (Lausanne) 2021;12:813067. https://doi. org/10.3389/fendo.2021.813067

Hackett G. Metabolic effects of testosterone therapy in men with type 2 diabetes and metabolic syndrome. Sexual Med Rev 2019;7(3):476-490. https://doi.org/10.1016/j.sxmr.2018.12.004

Wang A, Gerstein HC, Lee SF, et al. Testosterone and sex hormone-binding globulin in dysglycemic women at high cardiovascular risk: A report from the Outcome Reduction with an Initial Glargine Intervention Trial. Diab Vasc Dis Res 2021;18(2):14791641211002475. https://doi. org/10.1177/14791641211002475

Dev R, Del Fabbro E, Dalal S. Endocrinopathies and cancer cachexia. Curr Opin Support Palliat Care 2019;13(4):286-291. https://doi.org/10.1097/spc.0000000000000464

Maseroli E, Cellai I, Filippi S, et al. Anti-inflammatory effects of androgens in the human vagina. J Molecular Endocrinol 2020;65(3):109-124. https://doi.org/10.1530/jme-20-0147

org/10.1097/SLA.0b013e318146980e

Demling RH, Orgill DP. The anticatabolic and wound healing effects of the testosterone analog oxandrolone after severe burn injury. J Critical Care 2000;15(1):12-17. https://doi.org/10.1053/ jcrc.2000.0150012

Ring J, Heinelt M, Sharma S, Letourneau S, Jeschke MG. Oxandrolone in the Treatment of Burn Injuries: A Systematic Review and Meta-analysis. J Burn Care Res 2020;41(1):190-199. https:// doi.org/10.1093/jbcr/irz155

Bulger EM, Jurkovich GJ, Farver CL, Klotz P, Maier RV. Oxandrolone does not improve outcome of ventilator dependent surgical patients. Ann Surg 2004;240(3):472-478; Discussion 478-480. https://doi.org/10.1097/01.sla.0000137131.22608.e2

Gervasio JM, Dickerson RN, Swearingen J, et al. Oxandrolone in trauma patients. Pharmacother 2000;20(11):1328-1334. https://doi.org/10.1592/phco.20.17.1328.34889

Massa MG, David C, Jörg S, et al. Testosterone differentially affects t cells and neurons in 57. murine and human models of neuroinflammation and neurodegeneration. Am J Pathol 2017;187(7):1613-1622. https://doi.org/10.1016/j.ajpath.2017.03.006 58.

Jayaraman A, Lent-Schochet D, Pike CJ. Diet-induced obesity and low testosterone increase neuroinflammation and impair neural function. J Neuroinflam 2014;11(162). https://doi. org/10.1186/s12974-014-0162-y 59.

Ganesan K, Selvam R, Abhirami R, Raju KV, Manohar BM, Puvanakrishnan R. Gender differences

and protective effects of testosterone in collagen induced arthritis in rats. Rheumatol Int 2008;28(4):345-353. https://doi.org/10.1007/s00296-007-0446-y 60.

Pelegrin ÁF, de Paiva Gonçalves V, Carvalho JS, Spolidorio DMP, Spolidorio LC. Testosterone replacement relieves ligature-induced periodontitis by mitigating inflammation, increasing pro-resolving markers and promoting angiogenesis in rats: A preclinical study. Arch Oral Biol 61. 2023;146:105605. https://doi.org/10.1016/j.archoralbio.2022.105605

Magalhães SC, de Oliveira KA, Freiras PA, et al. High-dose Nandrolone decanoate induces

oxidative stress and inflammation in retroperitoneal adipose tissue of male rats. J Steroid 62. Biochemistry Molec Biol 2020;203:105728. https://doi.org/10.1016/j.jsbmb.2020.105728

Gomes FC, Chuffa LG, Scarano WR, Pinheiro PF, Fávaro WJ, Domeniconi RF. Nandrolone decanoate

and resistance exercise training favor the occurrence of lesions and activate the inflammatory 63. response in the ventral prostate. Andrology 2016;4(3):473-480. https://doi.org/10.1111/andr.12162

Oskui PM, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc 64. 2013;2(6):e000272. https://doi.org/10.1161/jaha.113.000272

Huang G, Tang E, Aakil A, et al. Testosterone dose-response relationships with cardiovascular risk

markers in androgen-deficient women: a randomised, placebo-controlled trial. J Clin Endocrinol 65. Metabol 2014;99(7):E1287-1293. https://doi.org/10.1210/jc.2013-4160

Maggio M, Snyder PJ, De Vita F, et al. Effects of transdermal testosterone treatment on inflammatory markers in elderly males. Endocrine Prac 2014;20(11):1170-1177. https://doi. 66. org/10.4158/EP13357.OR

WichmannMW,ZellwegerR,DeMasoCM,AyalaA,ChaudryIH.Mechanismofimmunosuppression

in males following trauma-hemorrhage. Critical role of testosterone. Arch Surg 1996;131(11):1186- 67. 1191; Discussion 1191-1192. https://doi.org/10.1001/archsurg.1996.01430230068012

Angele MK, Nitsch S, Knoferl MW, et al. Sex-specific p38 MAP kinase activation following 68. trauma-hemorrhage: Involvement of testosterone and estradiol. Am J Physiol-Endocrinol

Metabol 2003;285(1): E189-196. https://doi.org/10.1152/ajpendo.00035.2003

Guler N, Batyraliev T, Dulger H, et al. The effects of short term (3 weeks) testosterone treatment 69. on serum inflammatory markers in men undergoing coronary artery stenting. Int J Cardiol 2006;109(3):339-343. https://doi.org/10.1016/j.ijcard.2005.06.027

Zolin SJ, Vodovotz Y, Forsythe RM, et al. The early evolving sex hormone environment is 70. associated with significant outcome and inflammatory response differences after injury.

J Trauma Acute Care Surg 2015;78(3):451-457; Discussion 457-458. https://doi.org/10.1097/ ta.0000000000000550

Angele MK, Pratschke S, Hubbard WJ, Chaudry IH. Gender differences in sepsis: cardiovascular and immunological aspects. Virulence 2014;5(1):12-19. https://doi.org/10.4161/viru.26982

Ward CT, Boorman DW, Afshar A, et al. A Screening tool to detect chronic critically ill cardiac surgery patients at risk for low levels of testosterone and somatomedin C: A prospective observational pilot study. Cureus 2021;13(5):e15298. https://doi.org/10.7759/cureus.15298 Barrow RE, Dasu MR, Ferrando AA, et al. Gene expression patterns in skeletal muscle of thermally injured children treated with oxandrolone. Ann Surg 2003;237(3):422-428. https://doi. org/10.1097/01.Sla.0000055276.10357.Fb

Przkora R, Herndon DN, Suman OE. The effects of oxandrolone and exercise on muscle mass and function in children with severe burns. Pediatrics 2007;119(1):e109-e116. https://doi.org/10.1542/ peds.2006-1548

Porro LJ, Herndon DN, Rodriguez NA, et al. Five-year outcomes after oxandrolone administration in severely burned children: a randomised clinical trial of safety and efficacy. J Amn Coll Surgeons 2012;214(4):489-502; Discussion 502-484. https://doi.org/10.1016/j.jamcollsurg.2011.12.038 Herndon DN, Voigt CD, Capek KD, et al. Reversal of growth arrest with the combined administration of oxandrolone and propranolol in severely burned children. Ann Surg 2016;264(3):421-428. https://doi.org/10.1097/sla.0000000000001844

Sousse LE, Herndon DN, Mlcak RP, et al. Long-term administration of oxandrolone improves lung function in pediatric burned patients. J Burn Care Research 2016;37(5):273-277. https://doi. org/10.1097/BCR.0000000000000356

Gus EI, Shahrokhi S, Jeschke MG. Anabolic and anticatabolic agents used in burn care: What is known and what is yet to be learned. Burns 2020;46(1):19-32. https://doi.org/10.1016/j. burns.2018.03.009

Demling RH, DeSanti L. Oxandrolone induced lean mass gain during recovery from severe burns is maintained after discontinuation of the anabolic steroid. Burns 2003;29(8):793-797. https://doi. org/10.1016/j.burns.2003.08.003

Gala K, Desai V, Liu N, Omer EM, McClave SA. How to increase muscle mass in critically ill patients: lessons learned from athletes and bodybuilders. Curr Nutr Rep 2020;9(4):369-380. https://doi.org/10.1007/s13668-020-00334-0

Wang J, Wu T. Testosterone improves muscle function of the extensor digitorum longus in rats with sepsis. Bioscience Rep 2020;40(2). https://doi.org/10.1042/bsr20193342

Wischmeyer PE, Suman OE, Kozar R, Wolf SE, Molinger J, Pastva AM. Role of anabolic testosterone agents and structured exercise to promote recovery in ICU survivors. Curr Opin Crit Care 2020;26(5):508-515. https://doi.org/10.1097/mcc.0000000000000757

Weitzel LR, Sandoval PA, Mayles WJ, Wischmeyer PE. Performance-enhancing sports supplements: role in critical care. Crit Care Med 2009;37(10):S400-S409. https://doi.org/10.1097/ CCM.0b013e3181b6f2e6

Tomassini S, Abbasciano R, Murphy GJ. Interventions to prevent and treat sarcopenia in a surgical population: a systematic review and meta-analysis. BJS Open 2021;5(3). https://doi.org/10.1093/ bjsopen/zraa069

Remmers DE, Cioffi WG, Bland KI, Wang P, Angele MK, Chaudry IH. Testosterone: the crucial 72. hormone responsible for depressing myocardial function in males after trauma-hemorrhage. Ann

Surg 1998;227(6):790-799. https://doi.org/10.1097/00000658-199806000-00002

Bernhardt JA, d’Acampora AJ, Tramonte R, Serafim JD. Effect of post-natal castration on sepsis 73. mortality in rats. Acta Cirúrgica Brasileira 2007;22(1):22-29. https://doi.org/10.1590/s0102- 86502007000100004

Laubach VE, Foley PL, Shockey KS, Tribble CG, Kron IL. Protective roles of nitric oxide and 74. testosterone in endotoxemia: evidence from NOS-2-deficient mice. Am J Physiol 1998;275(6): H2211-H2218. https://doi.org/10.1152/ajpheart.1998.275.6.H2211

Gürer B, Turkoglu E, Kertmen H, Karavelioglu E, Arikok AT, Sekerci Z. Attenuation of 75. cerebral vasospasm and secondary injury by testosterone following experimental subarachnoid hemorrhage in rabbit. Acta Neurochir (Wien) 2014;156(11):2111-2120; discussion 2120. https:// doi.org/10.1007/s00701-014-2211-9

;125:27-42; Discussion 42-44.

Anstey MH, Rauniyar R, Fitzclarence E, et al. Muscle Growth and Anabolism in Intensive Care Survivors (GAINS) Trial: A pilot randomised controlled trial. Acute Crit Care 2022;37(3):295- 302. https://doi.org/10.4266/acc.2021.01767

Weber AE, Gallo MC, Bolia IK, Cleary EJ, Schroeder TE, Rick Hatch GF III. Anabolic androgenic steroids in orthopaedic surgery: Current concepts and clinical applications. J Am Acad Orthopaedic Surgeons Global Res Rev 2022;6(1). https://doi.org/10.5435/JAAOSGlobal-D-21-00156

Wolf SE, Edelman LS, Kemalyan N, et al. Effects of oxandrolone on outcome measures in the severely burned: A multicenter prospective randomised double-blind trial. J Burn Care Res 2006;27(2):131-139; Discussion 140-141. https://doi.org/10.1097/01.Bcr.0000202620.55751.4f Cochran A, Thuet W, Holt B, Faraklas I, Smout RJ, Horn SD. The impact of oxandrolone on length of stay following major burn injury: A clinical practice evaluation. Burns 2013;39(7):1374-1379. https://doi.org/10.1016/j.burns.2013.04.002

Pham TN, Klein MB, Gibran NS, et al. Impact of oxandrolone treatment on acute outcomes after severe burn injury. J Burn Care Res 2008;29(6):902-906. https://doi.org/10.1097/ BCR.0b013e31818ba14d

Altarrah K, Tan P, Acharjee A, et al. Differential benefits of steroid therapies in adults following major burn injury. J Plastic, Reconst Aesthetic Surg 2022;75(8):2616-2624. https://doi. org/10.1016/j.bjps.2022.04.007

Jeschke MG, Finnerty CC, Suman OE, Kulp G, Mlcak RP, Herndon DN. The effect of oxandrolone on the endocrinologic, inflammatory, and hypermetabolic responses during the acute phase postburn. Ann Surg 2007;246(3):351-360; Discussion 360-362. https://doi.

Ferrando AA, Sheffield-Moore M, Wolf SE, Herndon DN, Wolfe RR. Testosterone administration in severe burns ameliorates muscle catabolism. Crit Care Med 2001;29(10):1936-1942. https://doi. org/10.1097/00003246-200110000-00015

Gordy S, Kozar RA. Metabolism in the trauma patient. In: Davis KA, Rosenbaum SH, editors. Surgical metabolism: The metabolic care of the surgical patient. New York, NY: Springer New York; 2014. 97-109.s

Similar Articles

You may also start an advanced similarity search for this article.